Efficacy and Tolerability of Eight Antimicrobial Regimens in the Outpatient Treatment of Exacerbations of Chronic Obstructive Pulmonary Disease

METHODS: We performed an observational study including 343 COPD patients with probable bacterial exacerbation (Group A and Group B COPD patients) managed in an outpatient setting. Eight antibiotic regimens each used 10 days were evaluated: amoxicillin/clavulonic acid, doxycycline, cefuroxime, cefixime, clarithromycin, roxithromycin, ciprofloxacin, and moxifloxacin. All patients were followed up for 30 days, with an intermediate visits at 5, 7 and 10 days at which the duration of symptoms and the side-effects of the drug were evaluated.


Introduction
Chronic obstructive pulmonary disease (COPD) remains frequent and costly disease representing one of the principal demands of the public health worldwide. Inhaled tobacco smoke and other noxious particles, such as occupational exposures and smoke from biomass fuels, are the most important exogenous factors that influence disease development and progression [1].
The course of COPD can be affected by acute events characterized by a worsening of the patient's respiratory symptoms that is beyond normal day-today variations and leads to a change in medications, known as exacerbations [1]. These acute episodes, also characterized by increased airway inflammation and physiological deterioration, contribute greatly to the morbidity, the disease progression, and to the overall diminished quality of life in the subjects with COPD [2]. Respiratory infections, environmental and occupational exposures, discontinuation of the regular treatment, and worsening of the comorbid conditions are considered as causes of exacerbations, but in up 20% of the cases the cause of exacerbation remains unknown [2,3].
Respiratory infections account for up to 80% of exacerbations, of which bacterial infections are involved in around 50-70% of exacerbations [4]. Although the role of bacterial infection in acute exacerbations of COPD has been debated for many years, the investigations with newer research techniques (bronchoscopic, bacteriologic, and serologic studies) bolster the arguments that bacteria do cause exacerbations [5,6]. Respiratory infections account for up to 80% of exacerbations, of which bacterial infections are involved in around 50-70% of exacerbations [4]. The predominant bacteria recovered from the lower airways in patients with chronic bronchitis (CB) and COPD exacerbations are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Atypical bacteria, e. g.

Mycoplasma pneumoniae
and Chlamidia pneumoniae, are implicated in up to 10% of exacerbations, whereas viral infections, e. g. influenza and parainfluenza viruses, rhinovirus and adenovirus, cause up to 30% of episodes of infectious exacerbations [7,8]. On the other hand, studies in patients with COPD exacerbations have showed that the severity of the disease may be an important determinant of the type of microorganism. Namely, in mild exacerbations Streptococcus pneumoniae is predominant and as forced expiratory volume in one second (FEV 1 ) declines Haemophilus influenzae, and Moraxella catarrhalis become more frequent, whereas Pseudomonas aeruginosa and other enteric bacteria usual appear in patients with severe airway inflammation. The diagnosis of an exacerbation relies exclusively on the clinical presentation of the patient complaining of an acute change of symptoms (baseline dyspnea, cough, and/or sputum production) that is beyond normal day-to-day variation [1].
The criteria of Anthonisen [9] are still the most important classification system to identify patients likely to be infected with bacterial pathogens based on presentation of clinical symptoms [10,11]. A type I exacerbation was defined as a patient presenting with increased dyspnea, sputum volume and purulence. A type II exacerbation referred to a patient with two of these symptoms, while a type III exacerbation occurred when a patient had only one symptom with evidence of fever or upper airways infection.
According to the actual version of Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) [1], antibiotics should be given to patients with type I exacerbation (Evidence B); with type II exacerbation, if increased purulence of sputum is one of the two symptoms (Evidence C); as well as in patients who require mechanical ventilation (invasive or noninvasive) (Evidence B). The recommended length of antibiotic therapy is usually 5-10 days (Evidence D).
The goals of treatment for COPD exacerbations are to minimize the impact of the current exacerbation, as well as to prevent the development of subsequent exacerbation. Depending on the severity of an exacerbation and/or the severity of the underlying disease, an exacerbation can be managed in an outpatient or inpatient setting. More than 80% of exacerbations can be ambulatory treated with antibiotics. Potential indications for hospital management of the exacerbation include marked increase in symptoms intensity (e.g., sudden development of resting dyspnea), severe underlying COPD, onset of new physical signs (e.g., cyanosis, peripheral oedema), failure to respond to initial medical management, presence of serious comorbidities (e.g., heart failure, newly occurring arrhythmias), etc [1,12].
The present study aims to evaluate efficacy and safety of eight antibiotic regimens in the outpatient treatment of probable bacterial exacerbations in the COPD patients.

Material and Methods
An observational study including 343 outpatients classified as Group A and Group B COPD patients with an exacerbation of probably bacterial etiology, 192 males and 151 females, aged 35 to 78 years. All participants were informed about the study and their written consent was obtained.
The study was carried out in the period December 2012 -March 2013 at the Institute for Occupational Health of R. Macedonia, Skopje -WHO Collaborating Center and GA 2 LEN Collaborating Center. The study of the effects of various antimicrobial regimens on the clinical course of exacerbations of CB and COPD carried out by Miravittles et al [13] was used as a model.
Including criterion was the presence of a probable bacterial exacerbation in Group A and Group B COPD patients according to the combined COPD assessment [1], i.e. in patients with mild or moderate COPD according to the GOLD 2010 classification [14], which can be managed on outpatient basis. Diagnosis of the exacerbation was defined by the patient's symptoms, using the criteria described by Anthonisen et al. [9]. Probable bacterial etiology was established when the exacerbation was Anthonisen type I or type II if increased purulence of sputum was one of the two symptoms.
All patients underwent clinical examination, spirometry, blood gas measurements, ECG, and laboratory analysis. Chest X-ray was performed in a part of the patients by indications.
Excluding criterions were bacterial exacerbations in Group C and Group D COPD patients, patients with exacerbation type III or type II if increased purulence of sputum was not one of the two symptoms, patients with asthma, cystic fibrosis, malignancy or pneumonia, patients with known hypersensitivity to certain antibiotic and/or patients who fulfilled criteria for hospitalization.
After the diagnosis was established, the exacerbations were managed with antibiotics. Eight antibiotic regimens each used 10 days were evaluated: amoxicillin/clavulonic acid 875 mg/125 mg twice daily in 42 patients (12.2%), doxycycline 100 mg twice daily initially, then once daily in 43 patients (12.5%), cefuroxime 250 mg twice daily in 44 patients (12.8%), cefixime 400 mg once daily in 43 patients (12.5%), clarithromycin 500 mg twice daily in 42 patients (12.2%), roxithromycin 150 mg twice daily in 43 patients (12.5%), ciprofloxacin 500 mg twice daily in 44 patients (12.8%), and moxifloxacin 400 mg once daily in 42 patients (12.2%). Each antibiotic regimen was administered to the next patient who met including criterion in the mentioned cyclic order if there was no contraindication (i.e. known hypersensitivity) for its use. The patients were advised to continue the regular treatment of stable COPD, as well as to use short-acting bronchodilators when needed.
All patients were followed up for 30 days, with an intermediate visits at 5, 7 and 10 days at which they were asked about the duration of symptoms and the side-effects of the drug. The course of exacerbation was evaluated as a function of the resolution of the symptoms and the treatment was considered to be successful if cure or clinical improvement was achieved. The cure was defined as complete resolution of the cardinal symptoms, whereas the clinical improvement was defined as return of the symptoms to the baseline severity. In addition, spirometric parameters (FVC, FEV 1 , FEV 1 /FVC, MEF 25 , MEF 50 , MEF7 75 , and MEF  ) at the first visit and at the end of the treatment were compared. Relapse rates were registered during a 20 days follow-up period in the patients with remission of the symptoms.
Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 11.0 for Windows. Chi-square test was used for testing difference in the prevalence. Comparison of the mean time to relief of the symptoms and of the mean FEV 1 values was performed by independentsamples t-test. A P-value less than 0.05 was considered as statistically significant.

Results
The characteristics of the study subjects is shown Table 1.
The percentage of clinical success (i.e. clinical cure or resolution of the symptoms) was similar in the eight groups, varying from 69.8% with doxycycline to 80.9% with moxifloxacin ( Figure 1). The mean time to complete resolution of the symptoms or its return to the baseline severity varied from 6.2 days with amoxicillin/clavulonic acid to 5.7 days with moxifloxacin. The difference in the mean time to relief of symptoms between the eight groups was statistically non-significant ( Figure 2).  (Table 2). The values of spirometric parameters at the end of the treatment improved in all groups. Statistical difference of the pre-and post-treatment FEV 1 value was observed in all treatment groups (Table 3). Relapse during a 20 days follow-up period in the patients with remission of the symptoms was registered in the group receiving doxycycline, clarithromycin, and ciprofloxacin (2.3%, 2.4%, and 2.2%, respectively). In the other treatment groups there was not any case with relapse of the exacerbation in the follow-up period. The prevalence of the adverse events during the treatment varied from 6.7% with cefuroxime to 11.3% with ciprofloxacin with no statistical difference between the groups (Figure 3).
In any group there was not serious adverse effect that required discontinuation of the treatment. Gastrointestinal manifestations (nausea, vomiting, epigastric pain, and diarrhoea), followed by headache and dizziness were the most frequent adverse events (Table 4).

Discussion
Exacerbations of COPD have serious negative impact on patient quality of life, lung function, and socioeconomic costs so their prevention, early detection, and prompt treatment have a great importance in the management of the disease. The total of COPD-related expenses for outpatients care in the European Union countries is € 4.7 billion per year [15]. There is still debate about how exacerbations should be defined and graded, and their mechanisms are not well understood. The routine treatment of exacerbations with antibiotics remains controversial but there is no doubt that antibiotics are of benefit with exacerbations of a bacterial origin [16].
In the present study we compared the efficacy and tolerability of eight antibiotic regimens empirically administered for outpatient treatment of exacerbations of Group A and Group B COPD patients. The choice of the antimicrobial regimens was done in accordance to the actual recommendations [1,14,17]. The diagnosis of exacerbation was based on the presence of clinical symptoms and lung function measurements without microbiological evaluation of the sputum. According to the actual recommendations, sputum analysis should be reserved for patients with frequent exacerbations and for chronic purulent sputum in whom the presence of more virulent and/or more resistant bacteria is likely [3,18].
Examined subjects were divided in eight groups balanced in all their demographic, clinical, and functional characteristics, as well as in the severity of the exacerbations. We found a large proportion of active and passive smokers among examined subjects that was similar to its prevalence in adults documented in our previous studies [19,20].
The regional pattern of resistance to respiratory pathogens has a great impact on the choice of appropriate antibiotic regimen for treatment of acute exacerbations of COPD. Prevalence rates of beta-lactamase production of up to 40% for penicillinresistant Streptococcus pneumoniae have been reported in Spain and in the USA, and 58% in the Hungary, although in other countries, such as Germany and the UK, the prevalence rates are less than 5% [5,21,22]. Second-generation macrolides are considered to be the first-line treatment by Canadian Guidelines [23], whereas the Spanish authors [24] observed low efficacy of these agents due to the high rates of resistance (up to 35%) shown by Haemophilus influenzae. On the other hand, actual guidelines [14,25] recommend use of some older antibiotics (e.g. trimethoprime/ sulfamethoxasole and tetracycline) for which ten years ago by some authors [26] has been suggested not to be used in the treatment of exacerbations of chronic bronchitis and COPD. Results from the present study indicated high clinical success rate and time-course of the recovery that did not differ significantly between examined treatment options. Similar results were obtained in our previous study on efficacy and safety of five antimicrobial regimens (amoxicillin/clavulonic acid, cefuroxime, cefixime, clarithromycin, and ciprofloxacin) in the outpatient treatment of exacerbations of CB and COPD [27]. Similar effects of amoxicillin/clavulonic acid, cefuroxime, clarithromycin, and moxifloxacin were reported by the MOSAIC study [28], the IMPAC study [29], and the MAESTRAL study [30]. Similar results were also reported by Siempos et al. [31] in the meta-analysis of effectiveness of amoxicillin/clavulonate, macrolides, and quinolones in the treatment of acute exacerbations of CB. In the present study we found low proportion of the subjects with adverse events in all treatment groups similarly to the results of studies reviewed [32][33][34].
The present study had some limitations. The results should be viewed with caution, since the study was neither blinded nor randomised and, it is, therefore, subject to possible selection bias in favor of one treatment or another. On the other hand, relatively small number of the subjects in the different treatment groups could have certain implications on the data obtained and its interpretation. Relapses between days 10 and 30 appeared to be very infrequent due to the short time of observation. The strength of the study is the number of antibiotic regimens studied, as well as the studying of only exacerbated subjects with COPD, not exacerbated subjects with both CB and COPD.
In conclusion, in an observational study of efficacy and tolerability of eight antibiotic regimens (amoxicillin/clavulonic acid, doxycycline, cefuroxime, cefixime, clarithromycin, roxithromicin, ciprofloxacin, and moxifloxacin) in the outpatient treatment of the exacerbations in Group A and Group B COPD patients we found high clinical success rate, as well as similar time to relieve the symptoms of all regimens studied. Low incidence of adverse events indicated high tolerability of all treatment options. Our findings suggest that each of the examined options should be considered as a first choice antibiotic in the outpatient treatment of the exacerbations in Group A and Group B COPD patients.

Ethical Approval
The Ethical Committee of the Institute of Occupational Health of Republic of Macedonia, Skopje -WHO Collaborating Center and GA 2 LEN Collaborating Center gave approval for performing the study and publishing the results obtained (03-133/2-03.2013).

Authors Participations
JM participated in the study design, writing the protocol, data collection, managing the analyses of the study, and writing all versions of the manuscript. JKB participated in the study design, writing the protocol, managing the analyses of the study, as well as writing all versions of the manuscript. TP managed the literature searches and participated in the managing the analyses of the study. KV performed the statistical analysis and participated in the managing of the analyses of the study. SS, DM and SRK participated in the data collection. All authors read and approved the final manuscript.