Antibiotics in exacerbations of COPD: lessons from the past

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Abstract
The controversy about the use of the adequate antibiotic therapy for exacerbations of chronic obstructive pulmonary disease (COPD) continues. The new antibiotics, particularly the fluoroquinolones, have been included in most guidelines based on their excellent in vitro activity against respiratory pathogens, optimal bronchial penetration and convenient regimens of administration. However, clinical trials have only demonstrated equivalence of fluoroquinolones to traditional antibiotics and no conclusive evidence exists of their super- iority in clinical practice. In this context, we must either accept that no differences exist between antibiotics in this indication or that the majority of studies performed so far are inadequate to demonstrate them. The authors firmly believe that the second statement is more likely to be true than the first (1). In fact, observational studies suggested that moxifloxacin produces a faster resolu- tion of symptoms of exacerbation in COPD patients compared with amoxicillin-clavulanate, clarithromycin or cefuroxime (2). In addition, the direct costs of exacerbations treated with clarithromycin appeared to be higher than the costs associated with the use of moxifloxacin or amoxicillin- clavulanate, due to the higher rate of relapse with the macrolide (3). However, the definitive evidence of superiority derived from randomised, double-blind, clinical trials is scarce, and most guidelines recommend the new and supposedly more potent antibiotics for patients more at risk of relapse, based more on common sense rather than on scientific evidence, which is well recognised by the authors of the guidelines themselves (4, 5). In an attempt to demonstrate differences in outcomes between a fluoroquinolone, levofloxacin, and clarithromycin, LODE et al. (6) in this issue of the Journal present the results of a randomised, double-blind, clinical trial in patients with exacerbations of COPD. This trial presents two strengths, in comparison with most of the trials performed previously: the inclusion of COPD patients and the use of time to the next exacerbation as the primary outcome measure. The inclusion of patients with simple (nonobstructive) chronic bronchitis in antibiotic trials should be avoided. Patients with chronic bronchitis used to represent the milder end of the spectrum of bronchial disease caused by tobacco smoking and some or most may have normal lung function. The likelihood of bacterial infection as a cause of exacerbation decreases in patients with better lung function (7). Furthermore, the diagnosis of chronic bronchits is not reliable as an inclusion criterion. A recent study has shown that only 11.6% of individuals with self-reported chronic bronchitis really met the criteria for the disease, but even more surprisingly, only 12.5% of physician-confirmed cases of chronic bronchitis really fulfilled the criteria (8). It is surprising that, to be included in a clinical trial with bronchodilators, patients need to fulfil strict spirometric criteria, repeated several times and with the test performed by certified investigators under standard circumstances, whereas to be included in an antibiotic trial the patient just need to answer "yes" to the question "Did you have cough and sputum for at least 3 months in the last 2 yrs?", with the possibility of all sources of bias and the impossibility to verify the answer.

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