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Barcelona, Spain
Barcelona, Spain
Dr. Miravitlles is Senior Researcher and Dr. Torres is Director, Institut Clínic de Pneumologia i Cirurgia Toràcica.
Correspondence to: Antoni Torres, MD, FCCP, Servei de Pneumologia, Institut Clínic de Pneumologia i Cirurgia Toràcica (IDIBAPS), Hospital Clínic (escalera 12, planta 0), Villarroel 170, 08036 Barcelona, Spain; e-mail: atorres{at}clinic.ub.es
Antibiotic treatment of exacerbations of chronic bronchitis or COPD has been a matter of controversy for many years. The main reasons for this are the difficulties in defining exacerbations and in demonstrating their bacterial etiology. Furthermore, the inclusion of patients with simple chronic bronchitis in the antibiotic trials, ie, without airflow obstruction, in whom exacerbations are frequently a self-limited disease, has hampered the demonstration of the potential benefit of antibiotic therapy. During the last few years, some pivotal studies have demonstrated the relationship between exacerbations and increased bacterial counts,1 2 the acquisition of new bacterial strains,3 and increased associated bacterial-driven bronchial inflammation,4 which supports the bacterial etiology of some or most exacerbations of COPD. Furthermore, the persistence of bacteria after treatment of the exacerbation (residual bacterial colonization) influences the frequency and severity of the following exacerbations.5 Based on these findings, it is reasonable to assume that an antibiotic that induces faster and more complete eradication in vitro, such as moxifloxacin and other fluoroquinolones, will result in better clinical outcomes compared with other, less active antibiotics.6 However, most clinical trials of antibiotics have compared new drugs with standard therapy in patients with exacerbations who, in most cases, would have never required an antibiotic if treated in real-life conditions. These trials have been designed to fulfill the regulatory agency requirements, and they usually include patients who may be as young as 18 years old and a significant proportion of never-smokers.7 The question is, what kind of "chronic bronchitis" or "COPD" do these people have? A study8 has clearly shown that antibiotics are not better than placebo in these cases and, of course, no differences in efficacy are found between different antibiotics in this clinical setting. However, in well-designed studies, the superiority of antibiotics compared to placebo is clearly demonstrated, both in ambulatory9 and in severe patients.10
In fact, the aim of trials of antibiotics in exacerbations is to demonstrate that a new antibiotic is "at least as good as" the standard therapy. The design of such trials is based in the following aspects. First, exacerbations are considered to be similar to pneumonia; the equation is simple: there is supposedly one bacteria, one antibiotic is prescribed, and the results are measured and compared after 7 to 10 days of therapy. However, COPD is a chronic disease, with persistent symptoms, possible bacterial colonization, and recurrent episodes of exacerbation, which makes it very different from pneumonia. Second, bacterial infection and the need for antibiotic treatment are determined by the sole presence of type 1 exacerbation, ie, with the three cardinal symptoms described by Anthonisen et al.11 It must be kept in mind that patients in the former study had moderate-to-severe COPD with a mean FEV1 of only 33% predicted. Therefore, their results have never been validated and may not apply to patients with chronic bronchitis with normal or near-normal pulmonary function, even if they present a type 1 exacerbation. Furthermore, the heterogeneity of the population included in the trials is very high, including patients with several degrees of severity of the baseline pulmonary disease, and some of the trials even include patients with type 2 or 3 exacerbations who probably do not benefit from antibiotics.
The existing studies may be required for the pharmaceutical companies to launch their new antibiotics, but offer limited, if any, useful information to the clinician. In fact, if the new antibiotic is only "at least as good as" the standard therapy, why should we change our prescription habits? Some of the guidelines of treatment of exacerbations of COPD state that the recently introduced expensive new brands of antibiotics are usually not appropriate12 Fortunately, other guidelines recognize the evidence that treatment failure is more frequent in some well-defined, at-risk populations,13 14 and stratify the patients and the antibiotic treatment accordingly and recommend the new more potent agents, such as the new generation fluoroquinolones, in patients at greater risk for relapse.15 However, there is an urgent need for studies that clearly demonstrate the advantages of the newer, more potent antibiotics compared to the standard therapy to reduce the high rate of relapse of ambulatory treatment of exacerbations of COPD. It is clear that such studies should focus on patients with the highest probability of bacterial infection as the cause of the exacerbation and with risk factors for relapse. A combination of baseline characteristics of the disease, mainly an impaired pulmonary function,16 and characteristics of the exacerbation, namely type 1 exacerbation or purulence of sputum,17 will designate a population more likely to develop bacterial infection and experience a relapse. This population may be helpful in demonstrating the advantages of new, more potent antibiotics, if they really exist. Clearly, antibiotic trials which include patients < 40 years old, never-smokers, and/or subjects with nonobstructive chronic bronchitis should be avoided and should not be accepted by regulatory agencies. Furthermore, due to the characteristics of the disease, novel outcomes of clinical importance should be incorporated into the trials, such as the need for additional antibiotics, the time free from exacerbations,18 health-related quality of life,19 and economic analysis,20 among others.
The study included in this issue of CHEST(see page 953) has some merits and potential biases that deserve special consideration. In contrast to previous trials, the present study offers some examples of how antibiotic studies in exacerbations should be conducted. Although the main end point of the study was still to demonstrate equivalence, other novel end points were the need for repeated courses of antibiotics for the exacerbation as a surrogate marker of relapse, and the time free from exacerbation at 9 months of follow-up. In fact, patients receiving moxifloxacin presented a significantly longer period free from exacerbations, and the need for additional antibiotic therapy was significantly reduced compared with the comparative antibiotic regimens.
Another study, the Gemifloxacin Long-term Outcomes in Bronchitis Exacerbations study, demonstrated that the use of gemifloxacin compared to clarithromycin prolonged the time free from exacerbations, indicating that quinolones are beneficial in this important end point.6 Undoubtedly the time free from exacerbations is of paramount importance, since the frequency of exacerbations has been associated with a faster decline in pulmonary function,21 increased costs,22 and impairment in the quality of life.23 Another positive aspect of the current study is that the population is very well characterized. In contrast with most of the previous studies, all patients had to have a forced spirometry with an FEV1 of < 85% predicted to be included in the study. Other inclusion criteria were age > 45 years, a cumulative consumption of at least 20 pack-years of smoking, and more than two exacerbations the previous year. In addition, when patients had exacerbations, only type 1 exacerbations were considered for inclusion.
Patients included in the study were stratified according to a key variable such as the administration of steroids (both before randomization and during the exacerbation). Steroids before or during exacerbation modulate local and systemic inflammatory response and may be a confounding factor when evaluating the efficacy of antibiotics in exacerbations. In fact, the study showed that both clinical cure and clinical success were achieved in a significantly higher proportion of patients with moxifloxacin than comparator when no concomitant steroid treatment was given or no change in systemic steroid treatment was observed.
There are some potential drawbacks in the design of the study that deserve attention. Although the authors claimed that comparative drugs (cefuroxime, amoxicillin, and clarithromycin) are antibiotics administered "as standard" in clinical practice in exacerbations, this may not be the case in all European countries. In fact, recent Spanish guidelines on antibiotic treatment of exacerbations of COPD24 did not include any of these antibiotics as first-line treatment, the reason being the current rates of resistance of Streptococcus pneumoniae and Haemophilus influenzae to these three antibiotics, which may apply to other European countries.25 In addition, the authors pooled the three comparators together in the analysis, which exhibit very different antimicrobial spectrum and activity. From their results, it can be concluded that moxifloxacin is superior to the three comparators considered together, but not to any of them considered individually. It could be that the superiority of moxifloxacin is due to the poor results obtained with one of the comparators, thereby affecting the mean efficacy of the whole group, whereas the other two antibiotics perform at least as well as moxifloxacin. One previous study26 has shown that treatment of exacerbations with amoxicillin resulted in higher relapse rates than treatment with quinolones, macrolides, or amoxicillin-clavulanate. It would be necessary to stratify the results for each of the comparators for valid conclusions to be drawn.
Low FEV1 is an important variable that has been related as a risk factor for microorganisms such as H influenzae and Gram-negative bacilli, including Pseudomonas.16 Although the FEV1 was recorded in all patients, results on clinical and bacteriological efficacy were not stratified according FEV1. The superiority of moxifloxacin may be due to better results in the more severe population or may also extend to the whole spectrum of severity of COPD. Results in different severity subgroups of patients would have been useful to establish the place of moxifloxacin in the management guidelines of exacerbated COPD.
To some extent, COPD can be considered an orphan disease. In fact, most (if not all) of the drugs used in the stable phase of the disease have been initially developed for treating asthma. Similarly, most trials aimed at demonstrating the efficacy of antibiotics in exacerbations have been modeled on pneumonia studies. Research in both asthma and pneumonia has been the inspiration of subsequent studies in COPD in many cases. Furthermore, a specific approach to the disease that takes into account its unique characteristics has seldom been used by researchers. In this respect, future studies should imitate some of the strengths of the current study and improve its drawbacks by selecting patients with a lower FEV1, stratified by comparators and the severity of the baseline lung function. Clearly, no more equivalence studies are required, and please forget about chronic bronchitis—COPD is the real disease. Who can rely on a diagnosis based on the symptoms a patient had (or said he had) 2 years ago?
References
This article has been cited by other articles:
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  F. J. Martinez, R. F. Grossman, N. Zadeikis, A. C. Fisher, K. Walker, M. E. Ambruzs, and A. M. Tennenberg Patient stratification in the management of acute bacterial exacerbation of chronic bronchitis: the role of levofloxacin 750 mg Eur. Respir. J., June 1, 2005; 25(6): 1001 - 1010. [Abstract] [Full Text] [PDF]
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M. Miravitlles and A. Torres Antibiotics in exacerbations of COPD: lessons from the past Eur. Respir. J., December 1, 2004; 24(6): 896 - 897. [Full Text] [PDF]
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H. Lode, J. Eller, A. Linnhoff, M. Ioanas, and the Evaluation of Therapy-Free Interval in COPD Pa Levofloxacin versus clarithromycin in COPD exacerbation: focus on exacerbation-free interval Eur. Respir. J., December 1, 2004; 24(6): 947 - 953. [Abstract] [Full Text] [PDF]
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