Antibiotics and reduced risk of COPD re-exacerbations

Abstract

Evaluation of: Roede BM, Bresser P, Prins JM et al. Reduced risk of next exacerbation and mortality associated with antibiotic use in COPD. Eur. Respir. J. 33(2), 282–288 (2009).

Chronic obstructive pulmonary disease is a progressive disease of the airways in which respiratory symptoms aggravate transitorily during disease exacerbations. The treatment of the disease in its stable state is the most important factor in reducing related morbidity, but exacerbation therapy might also impact on subsequent re-exacerbation. The effects of adding antibiotics to oral corticosteroids at the first exacerbation are analyzed in the discussed paper and it is demonstrated that such a regimen might be associated with a lower risk of re-exacerbation and with a potential reduction of chronic obstructive pulmonary disease morbidity and mortality. However, the analysis is only based on data at primary care level and, hence, should be interpreted with caution for several reasons, discussed in the paper. Furthermore, such results can represent a useful starting point for a subsequent study on this aspect, which is very important for clinical practice and surprisingly less investigated.

Keywords::

• antibiotic
• chronic obstructive pulmonary disease
• chronic obstructive pulmonary disease exacerbation
• morbidity
• re-exacerbation

Chronic obstructive pulmonary disease (COPD) is a progressive disease of the airways in which exposure to smoking or other noxious agents are recognized as risk factors [1]. Inflammation in the airways, induced by certain risk factors, impairs the lung function with consequent airflow limitation and development of respiratory symptoms, such as dyspnea and cough, which aggravate progressively as disease advances and transitorily during disease exacerbation [2]. COPD exacerbations are usually caused by infectious agents and mainly by bacteria although, sometimes, symptom exacerbations are due to noninfectious causes.

Chronic obstructive pulmonary disease (COPD) exacerbations can be treated with oral bronchodilators, corticosteroids and antibiotics but their combination is not always necessary based on the low severity of exacerbation and on the lack of identification of a bacterial strain. On the other hand, however, the severity classification of COPD exacerbation is still based on minimal criteria and, therefore, it is difficult to ascertain when antibiotics are indicated. This means that, in some cases, antibiotics are prescribed anyway once the diagnosis of COPD exacerbation is documented, even if they are not necessarily required or, on the contrary, the antibiotics are not prescribed although they might be useful.

A meta-analysis performed on data from studies in which COPD exacerbation was defined as an increase in cough with sputum volume and purulence showed that antibiotic therapy, irrespective of factors described previously, reduced mortality, treatment failure and sputum purulence risks significantly [3].

Although the correct treatment of the disease in stable state has the most substantial effect on subsequent morbidity, adequate exacerbation therapy might also influence it by reducing the re-exacerbation risk [4]. This is particularly important for bacterial exacerbation, which occurs most frequently in patients with more advanced COPD and is associated with the highest risk of hospitalization and health resources utilization [5].

The effects of adding antibiotics to oral corticosteroids at the first COPD exacerbation on subsequent exacerbations was analyzed in the study performed by Roede and coworkers, based on data regarding COPD exacerbations treated at primary care level in The Netherlands [1].

Methods & results

This was a study using patient data retrieved from the Second Dutch National Survey of General Practice (DNSGP-2) performed in 2001. Data on COPD-related morbidity, mortality and prescriptions was analyzed in 842 patients experiencing at least one COPD exacerbation over 1 year and who met the analysis criteria. COPD exacerbation was defined as prescription of a short-course of corticosteroids, with or without antibiotics. The median follow-up period after first exacerbation was 1353 days (interquartile range: 791–1649 days).

A total of 4038 exacerbations were recorded, 56% of whom were treated only with oral corticosteroids (OC) and 46% with oral corticosteroids and antibiotics (OCA).

A total of 842 patients were recorded as having at least one exacerbation, 404 patients were being treated for the first exacerbation with OC and the remaining 438 with OCA. There were no differences seen in terms of gender, age, maintenance inhaled corticosteroids, medications for comorbid conditions and follow-up period between the OC and OCA group.

The antibiotics most commonly administered for the first exacerbation were doxycyclin in 218 patients, aminopenicillins (amoxicillin-clavulanate and amoxicillin) in 141 patients, macrolides in 68 patients and fluoroquinolones in 11 patients.

A total of 595 (52% OC, 48% OCA) patients experienced a second exacerbation. The median time to second exacerbation was comparable in OC and OCA groups (331 vs 312 days; p = 0.31) and comparable percentages of patients in both groups experienced a second exacerbation after 6 months (27% in OC and 23% in OCA ) or after 1 year (52% in OC and 54% in OCA).

The third exacerbation was reported in 450 patients, the median duration of time between the second and the third exacerbation being significantly shorter in OCA group 189 versus 258 days (p < 0.01). After 1 year from the second exacerbation, 69 and 61% of the OC and OCA groups, respectively, experienced the third exacerbation. The hazard ratio (HR) for a new exacerbation according to OC/OCA treatment was 0.73 for OCA compared with OC (95% CI: 0.63–0.84), and 0.72 in the first 3 months after treatment. Antibiotic use without OC reduced the risk of a subsequent exacerbation to 0.56.

In total, 62 patients (14%) died after the first exacerbation in the OCA group and 82 patients (20%) in the OC group (p = 0.020). HR of all-cause mortality after OCA treatment was 0.67 when compared with OC.

Discussion

This study demonstrates that in primary care treatment of COPD exacerbations with OCA might reduce the risk of re-exacerbation, and might be associated with a lower rate of COPD exacerbations and a reduction of mortality risk.

This analysis of COPD-related morbidity based on general practitioners’ prescription records is very interesting and relevant for the general practice level as it is based upon data that was retrieved from the GP’s Dutch database. The same team of authors reported in a previous study, based on pharmacy prescription dispensing data, that addition of antibiotics to OC reduced the exacerbation rate and improved survival [1].

Such information should be interpreted with caution for several reasons. First, they are pooled analyses of prescription data that only take into account the diagnosis of COPD exacerbation and the treatment given with OC whether or not it is associated with antibiotics. Second, the severity of exacerbation is not analyzed and this would be an important confounding factor. It is not mentioned whether or not the duration of treatment is standardized. The degree of lung function impairment in the year of the first exacerbation would have also been interesting to be considered as an item of subset analysis of efficacy of OCA, as the severity of stable-state disease might also influence the severity of exacerbation, the types of bacterial strain and, hence, the type of antibiotic and the duration of antibiotic therapy. Current smoking status and number of years with COPD diagnosis are also not taken into account. Smoking status in particular would have been the most interesting as it is associated with an increased risk of airway colonization, particularly with Hemophilus influenzae, and hence, with an increased risk of bacterial exacerbations.

Expert commentary & five-year view

Chronic obstructive pulmonary disease exacerbation is usually characterized by an increase of dyspnea, which can be associated with an increase of sputum production and/or with sputum purulence. The pharmacological therapy of COPD exacerbation is mainly represented by three classes of agents: bronchodilators, antibiotics and OC. In the less severe exacerbations, bronchodilators and short-course OC are usually effective in reducing dyspnea level, whereas in more severe COPD exacerbations, especially if they occur in more advanced COPD stages, the addition of antibiotics is mandatory.

The role of the latter in reducing the COPD exacerbations risk depends on their sterilizing efficacy in the airways; that is, on their role in reducing the risk of bronchial bacterial recolonization. But this also depends on the type of antibiotic selected, treatment duration and the degree of inflammation and damage in the airways in both stable and exacerbated states. Overall, the addition of antibiotics to the OC should be beneficial in reducing the risk of the subsequent exacerbations but not if applied universally, that is, irrespective of exacerbation severity or disease stage. On the other hand, at primary care level it can be expected that milder COPD exacerbations are treated and that the combined OCA regimen is less used. The data in this study show that comparable percentages of patients received OC and OCA and that the combined regimen might be more effective even in reducing the milder COPD-related morbidity.

More reliable data on the efficacy of adding antibiotics to OCs as a standardized exacerbation therapy, irrespective of the exacerbation or underlying disease severity or, on the contrary, from which stage of exacerbation severity, the addition of antibiotics to OC is most effective in reducing the subsequent risk of exacerbation can be obtained only with clinical studies. Such studies require a more rigorous definition of exacerbation and its severity, and inclusion of other outcome measures related to the stable disease.

The information derived from prescription data and the results discussed earlier are very interesting as a starting point in further evaluating the impact of an exacerbation therapy regimen on subsequent exacerbations.

Key issues

• • Oral corticosteroids alone or in combination with antibiotics are commonly used to treat chronic obstructive pulmonary disease exacerbations at a primary care level.

• • The impact of treating the first exacerbation with antibiotics and oral corticosteroids on the subsequent exacerbations is not well known.

• • The use of this combined regimen might be associated with reduced risk of subsequent exacerbations.

• • More reliable data can be gathered from clinical studies in which severity of treated exacerbation and of the underlying disease are analyzed.

• • The analysis of subsequent morbidity based on exacerbation prescription data is, however, useful as the basis for the further evaluation of this relationship.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.