van Velzen P, Ter Riet G, et al.

Doxycycline for outpatient-treated acute exacerbations of COPD: a randomised double-blind placebo-controlled trial.
Lancet 2017;5(6):492-499.

Treating outpatient COPD exacerbations with antibiotics remains controversial. In 1987, Anthonisen and colleagues from Manitoba, Canada, found a higher symptom resolution rate in those given antibiotics. The effect was most pronounced when three symptoms were present – increased shortness of breath, sputum volume and sputum purulence – leading to the so-called Anthonisen criteria for determining which patients should be given antibiotics.1 Other trials have provided inconsistent results, and a Cochrane review showed that for currently available antibiotics there was no improvement in treatment failure rates.2

To try to find definitive evidence, Patricia van Velzen and colleagues prospectively enrolled 885 patients with mild to severe COPD across primary and secondary care in the Netherlands. Over two years, 305 patients experienced exacerbations and were randomised at this point to either corticosteroids and doxycycline or corticosteroids and placebo. Exclusion criteria included a temperature greater than 38.5°C.

There were no differences in time to next exacerbation (148 days with doxycycline and 161 days with placebo, p=0.91) or total number of exacerbations over the next two years (both n=2, p=0.91) between the groups. Stratifying by age, COPD severity (GOLD stage), smoking status, previous exacerbation frequency or sputum purulence did not affect this negative finding. However, by day 21 only 21% in the antibiotic group had failed to resolve compared with 31% in the placebo group, a finding that did not quite meet statistical significance alone (p=0.07), but when combined with the previous systematic review showed a relative risk of 0.77 for treatment non-response (p=0.01). The number needed to treat to prevent one treatment failure at day 21 was 10.9 patients. Of note, however, there was an unexplained doubling of cardiovascular events from 7% to 14% (p=0.06).3

In patients without fever treated for an exacerbation as an outpatient, antibiotics did not prolong the time to next exacerbation, but when previous evidence is considered the results lend cautious support for antibiotic use to hasten symptom resolution for around one in eleven patients. We are not currently able to identify the patients who will respond, with sputum purulence not accurately predicting antibiotic response. Ultimately, COPD exacerbations are heterogeneous events so future research should focus on identifying biomarkers of bacterial exacerbations to determine who is most likely to benefit from antibiotic therapy.

Dr Gareth Hynes is a clinical research fellow in severe asthma at the University of Oxford.

This project was initiated and funded by Teva Respiratory. Teva have had no influence over content. Topics and content have been selected and written by independent experts.