Review question
Which preventative antibiotic is effective and safe for reducing exacerbations, improving quality of life, and reducing serious side effects in people with COPD?
What is COPD?
COPD is a lung condition that can cause long-term breathing problems. Symptoms include shortness of breath, cough, and sputum production. Flare-ups (so-called exacerbations) can be triggered by infection or inflammation, causing worsening symptoms and lung damage. Frequent exacerbations can lead to reduced quality of life and can increase the risk of death.
Why did we do this review?
We wanted to find out if one type of preventative antibiotic was better than another in reducing exacerbations, improving quality of life, and reducing side effects. We did this by using information from two previous reviews and comparing different antibiotics with each other, and with a control treatment (called placebo), by creating networks. As information was limited, the networks allowed us to combine information and determine the best preventative antibiotics by ranking them in order of ability to reduce exacerbations, improve quality of life, and reduce serious side effects.
What evidence did we find?
We tested three types of antibiotics: macrolides, quinolones, and tetracyclines. Macrolides were better in reducing exacerbations compared to control treatment. There was no clear difference in exacerbations when quinolone or tetracycline was compared with a control treatment. Tetracyclines were ranked lower than placebo in reducing exacerbations. We used the data for each antibiotic group to rank antibiotic groups in order of their ability to reduce exacerbations. We found that macrolides ranked first, followed by quinolones (second). Tetracyclines were ranked fourth and were not better than control treatment (ranked third).
Macrolides improved quality of life compared with control treatment. Quinolones did not appear to impact quality of life, and tetracyclines may have been associated with worsening quality of life compared to control treatment.
Macrolides were more effective in reducing serious unwanted events. There was no clear benefit for serious unwanted events with quinolone, tetracycline, or combined macrolide plus tetracycline compared with control treatment.
We could not clearly show benefit or harm of preventative antibiotic use for microbial resistance.
Quality of the evidence
We did not find any concerns about the ways in which studies were carried out, except that for some studies, people collecting the information knew (1) which patient was included in which treatment group, and (2) patient results when treatments were completed. Overall, the numerical information was robust and was unlikely to be influenced by differences noted between individual studies.
Conclusion
We found that exacerbations were reduced, quality of life was improved, and unwanted events were fewer with macrolides compared with control treatment. We could not determine whether quinolones or tetracyclines were of benefit compared with control treatment. Macrolides were ranked highest, followed by quinolones, which ranked second. Tetracyclines were no better than control treatment (ranked fourth and third, respectively). Although these NMAs show some benefit of using macrolides, they are based on a limited number of studies, and concerns remain about antibiotic resistance with long-term use of antibiotics.
This NMA evaluated the safety and efficacy of different antibiotics used prophylactically for COPD patients. Compared to placebo, prolonged administration of macrolides (ranked first) appeared beneficial in prolonging the time to next exacerbation, improving quality of life, and reducing serious adverse events. No clear benefits were associated with use of quinolones or tetracyclines. In addition, antibiotic resistance was a concern and could not be thoroughly assessed in this review. Given the trade-off between effectiveness, safety, and risk of antibiotic resistance, prophylactic administration of antibiotics may be best reserved for selected patients, such as those experiencing frequent exacerbations. However, none of the eligible studies excluded patients with previously isolated non-tuberculous mycobacteria, which would contraindicate prophylactic administration of antibiotics, due to the risk of developing resistant non-tuberculous mycobacteria.
Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterised by persistent respiratory symptoms and airflow limitation. Acute exacerbations punctuate the natural history of COPD and are associated with increased morbidity and mortality and disease progression. Chronic airflow limitation is caused by a combination of small airways (bronchitis) and parenchymal destruction (emphysema), which can impact day-to-day activities and overall quality of life. In carefully selected patients with COPD, long-term, prophylactic use of antibiotics may reduce bacterial load, inflammation of the airways, and the frequency of exacerbations.
To assess effects of different prophylactic antibiotics on exacerbations, quality of life, and serious adverse events in people with COPD in three separate network meta-analyses (NMAs), and to provide rankings of identified antibiotics.
To identify eligible randomised controlled trials (RCTs), we searched the Cochrane Airways Group Specialised Register of trials and clinical trials registries. We conducted the most recent search on 22 January 2020.
We included RCTs with a parallel design of at least 12 weeks' duration evaluating long-term administration of antibiotics prophylactically compared with other antibiotics, or placebo, for patients with COPD.
This Cochrane Review collected and updated pair-wise data from two previous Cochrane Reviews. Searches were updated and additional studies included. We conducted three separate network meta-analyses (NMAs) within a Bayesian framework to assess three outcomes: exacerbations, quality of life, and serious adverse events. For quality of life, we collected data from St George's Respiratory Questionnaire (SGRQ). Using previously validated methods, we selected the simplest model that could adequately fit the data for every analysis. We used threshold analysis to indicate which results were robust to potential biases, taking into account each study’s contributions to the overall results and network structure. Probability ranking was performed for each antibiotic class for exacerbations, quality of life, and serious adverse events.
Characteristics of studies and participants
Eight trials were conducted at multiple sites that included hospital clinics or academic health centres. Seven were single-centre trials conducted in hospital clinics. Two trials did not report settings. Trials durations ranged from 12 to 52 weeks. Most participants had moderate to severe disease. Mean age ranged from 64 years to 73 years, and more males were recruited (51% to 100%). Forced expiratory volume in one second (FEV₁) ranged from 0.935 to 1.36 L. Most participants had previous exacerbations. Data from 12 studies were included in the NMAs (3405 participants; 16 treatment arms including placebo). Prophylactic antibiotics evaluated were macrolides (azithromycin and erythromycin), tetracyclines (doxycyclines), quinolones (moxifloxacin) and macrolides plus tetracyclines (roxithromycin plus doxycycline).
Risk of bias and threshold analysis
Most studies were at low risk across domains, except detection bias, for which only seven studies were judged at low risk. In the threshold analysis for exacerbations, all comparisons in which one antibiotic was compared with another were robust to sampling variation, especially macrolide comparisons. Comparisons of classes with placebo were sensitive to potential bias, especially macrolide versus placebo, therefore, any bias in the comparison was likely to favour the active class, so any adjustment would bring the estimated relative effect closer to the null value, thus quinolone may become the best class to prevent exacerbations.
Exacerbations
Nine studies were included (2732 participants) in this NMA (exacerbations analysed as time to first exacerbation or people with one or more exacerbations). Macrolides and quinolones reduced exacerbations. Macrolides had a greater effect in reducing exacerbations compared with placebo (macrolides: hazard ratio (HR) 0.67, 95% credible interval (CrI) 0.60 to 0.75; quinolones: HR 0.89, 95% CrI 0.75 to 1.04), resulting in 127 fewer people per 1000 experiencing exacerbations on macrolides. The difference in exacerbations between tetracyclines and placebo was uncertain (HR 1.29, 95% CrI 0.66 to 2.41). Macrolides ranked first (95% CrI first to second), with quinolones ranked second (95% CrI second to third). Tetracyclines ranked fourth, which was lower than placebo (ranked third). Contributing studies were considered as low risk of bias in a threshold analysis.
Quality of life (SGRQ)
Seven studies were included (2237 participants) in this NMA. SGRQ scores improved with macrolide treatment compared with placebo (fixed effect-fixed class effect: mean difference (MD) -2.30, 95% CrI -3.61 to -0.99), but the mean difference did not reach the minimally clinical important difference (MCID) of 4 points. Tetracyclines and quinolones did not improve quality of life any more than placebo, and we did not detect a difference between antibiotic classes.
Serious adverse events
Nine studies were included (3180 participants) in the NMA. Macrolides reduced the odds of a serious adverse event compared with placebo (fixed effect-fixed class effect: odds ratio (OR) 0.76, 95% CrI 0.62 to 0.93). There was probably little to no difference in the effect of quinolone compared with placebo or tetracycline plus macrolide compared with placebo. There was probably little to no difference in serious adverse events between quinolones or tetracycline plus macrolide. With macrolide treatment 49 fewer people per 1000 experienced a serious adverse event compared with those given placebo. Macrolides ranked first, followed by quinolones. Tetracycline did not rank better than placebo.
Drug resistance
Ten studies reported drug resistance. Results were not combined due to variation in outcome measures. All studies concluded that prophylactic antibiotic administration was associated with the development of antimicrobial resistance.