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. 2021 Jan 15;1(1):CD013198.
doi: 10.1002/14651858.CD013198.pub2.

Prophylactic antibiotics for adults with chronic obstructive pulmonary disease: a network meta-analysis

Sadia Janjua  1 , Alexander G Mathioudakis  2   3 , Rebecca Fortescue  1 , Ruth Ae Walker  4 , Sahar Sharif  4 , Christopher Jd Threapleton  5 , Sofia Dias  4
Affiliations

Prophylactic antibiotics for adults with chronic obstructive pulmonary disease: a network meta-analysis

Sadia Janjua et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: 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.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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.

Authors' conclusions: 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.

PubMed Disclaimer

Conflict of interest statement

SJ is employed full‐time by an NIHR Programme Grant to complete work on this Cochrane Review.

SD was a co‐applicant on a grant whereby Pfizer partially sponsored a researcher but was not sponsored by Pfizer herself.

CT was employed part‐time in 2017‐18 by an NIHR Programme Grant to complete work on this Cochrane Review. He is currently a Specialty Registrar in Clinical Pharmacology and Therapeutics and General Internal Medicine.

AGM has received a research grant for an investigator‐initiated study by Boehringer Ingelheim. He has received honoraria from Boehringer Ingelheim and GlaxoSmithKline, which are not related to the content of this manuscript.

RF is employed part‐time by an NIHR Programme Grant to complete work on this Cochrane Review and is a qualified general practitioner.

RW is a research fellow employed by the University of York.

SS is a research fellow employed by the University of York.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Exacerbations: network diagram of interventions and classes. Treatment abbreviations are defined in Table 4. The size of the nodes is proportionate to the number of participants assigned to the intervention. The thickness of the lines is proportionate to the number of randomised trials that studied the respective comparison.
4
4
Exacerbations: forest plot of relative effects for each class comparison. Values less than 1 favour the first names class.
5
5
Exacerbations: plot of rank probabilities for each class.
6
6
Exacerbations: forest plot with threshold analysis for the log‐HR of exacerbations for each class. Base case optimal treatment set is 2. Class codes: 1 = placebo; 2 = macrolide; 3 = tetracycline; 4 = quinolone. Comparisons are macrolide versus placebo (2 versus 1); tetracycline versus placebo (3 versus 1); quinolone versus placebo (4 versus 1); tetracycline versus macrolide (3 versus 2); quinolone versus macrolide (4 versus 2); quinolone versus tetracycline (4 versus 3).
7
7
Quality of life: SGRQ network map.
8
8
Change from baseline in SGRQ: forest plot of relative effects for each class comparison. Values less than 0 favour the first named class.
9
9
Change from baseline in SGRQ: plot of rank probabilities for each class.
10
10
Serious adverse events: forest plot of relative effects for each class comparison. Values less than 1 favour the first named class.
11
11
Serious adverse events: network map.
12
12
Serious adverse events: plot of rank probabilities for each antibiotic class
See this image and copyright information in PMC

Comment in

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