Thorax Online First, published on August 5, 2008 as 10.1136/thx.2008.095349 Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from Antibiotic treatment is associated with reduced risk of a subsequent exacerbation in : A historical population-based cohort study

Berendina M. Roede1,3, Paul Bresser2, Patrick J.E. Bindels3, Annemieke Kok5, Maria Prins1,5, Gerben ter Riet3,6, Ronald B. Geskus4, Ron M.C. Herings7, and Jan M. Prins1

1Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, and Center for Infection and Immunity Amsterdam (CINIMA), 2Department of Pulmonology, 3Department of General Practice, 4Department of Clinical epidemiology and Biostatistics, Academic Medical Centre-University of Amsterdam, Amsterdam; 5Municipal Health Service, Cluster Infectious Diseases, Amsterdam, The Netherlands; 6Horten Centre, University of Zurich, Zurich, Switzerland; 7PHARMO Institute, Utrecht, The Netherlands.

Keywords: COPD, Exacerbation, Antibiotics, Corticosteroids

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on September 30, 2021 by guest. Protected copyright.

Corresponding author BM Roede Academic Medical Centre – University of Amsterdam Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, and Centre for Infection and Immunity Amsterdam (CINIMA), F4-217 Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Phone: +31-205664380 Fax: +31-206972286 e-mail: [email protected]

Copyright Article author (or their employer) 2008. Produced by BMJ Publishing Group Ltd (& BTS) under licence. Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from 1 Abstract 2 3 Objectives We evaluated the risk of a subsequent exacerbation after treatment of an 4 exacerbation with oral corticosteroids without (OS) or with antibiotics (OSA), in a historical 5 population-based cohort study comprising patients using maintenance for 6 obstructive lung disease. 7 8 Methods The Pharmo database includes drug-dispensing records of more than 2 million 9 subjects in the Netherlands. Eligible were patients ≥ 50 years who in 2003 were dispensed ≥ 10 2 prescriptions of daily used inhaled β2-agonists, , and/or corticosteroids, and 11 experienced at least one exacerbation before 1 January 2006. Exacerbation was defined as a 12 prescription of OS or OSA. We compared the times to the second and third exacerbations 13 using Kaplan-Meier survival analysis. Independent determinants of new exacerbations were 14 identified using multivariable Cox recurrent event survival analysis. 15 16 Results Of 49,599 patients using maintenance medication, 18,928 patients had at least one 17 exacerbation; in 52% antibiotics had been added. OS and OSA groups were comparable for 18 potential confounding factors. The median time to the second exacerbation was 321 days in 19 the OS group and 418 days in the OSA group (p< 0.001); and between the second and third 20 exacerbation 127 vs. 240 days (p<0.001). The protective effect of OSA was most pronounced 21 during the first three months following treatment (hazard ratio 0.62; 99%CI 0.60 – 0.65). In 22 the OSA group mortality during follow-up was lower (HR 0.82; 99% CI 0.66-0.98). 23 24 Conclusion Treatment with antibiotics in addition to oral corticosteroids was associated with 25 a longer time to the next exacerbation, and a decreased risk of developing a new 26 exacerbation.

27 http://thorax.bmj.com/ 28 29 30 31 32 33 34 on September 30, 2021 by guest. Protected copyright. 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50

2 Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from 1 Introduction 2 3 The mainstay of treatment of exacerbations of COPD consists of oral corticosteroids and 4 antibiotics. The use of corticosteroids in this situation is well-accepted, but the role of 5 antibiotics in exacerbations of COPD is still under debate. Patients with severe exacerbations, 6 characterised by severe symptoms, and/ or patients with a low baseline expiratory flow rate 7 are considered to benefit from antibiotic treatment.1-3 A recent Cochrane review supports the 8 use of antibiotics for short term benefits in patients with an exacerbation with increased 9 cough and sputum purulence who are moderately or severely ill.4 Studies conducted in 10 general practice showed no advantage of antimicrobial treatment.5,6,7 Given the inconclusive 11 results from the literature, guidelines differ in their recommendations.8-12 The main concern 12 with antibiotic use is a rise of antimicrobial resistance, which correlates well with the overall 13 antibiotic use in the community.13 14 15 The Dutch Pharmo database contains extensive data on pharmacy dispensing records from 16 community pharmacies and hospital discharge records of more than two million residents of 17 the Netherlands.14 This gave us the unique opportunity to evaluate the long-term effects of 18 treatment of exacerbations in a large patient group using maintenance medication for 19 obstructive lung disease. In particular, we compared the risk of a subsequent exacerbation 20 after treatment with oral corticosteroids without or with antibiotics. http://thorax.bmj.com/ on September 30, 2021 by guest. Protected copyright.

3 Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from 1 Methods 2 3 Data sources 4 Data for this study were obtained from the PHARMO database.14 This population-based 5 database includes pharmacy dispensing records from community pharmacies and hospital 6 discharge records of more than two million residents of 50 regions scattered over the 7 Netherlands. Data are representative for the Netherlands. Both prescriptions from General 8 Practitioners and outpatients are registered. For all residents, the drug-dispensing histories are 9 linked to the hospital discharge records of the same patient, using a probabilistic algorithm, 10 based on characteristics such as date of birth, gender, and a code for the GP.15 The 11 computerised drug-dispensing histories contain data concerning the dispensed drug and 12 dispensing date. Drugs are coded according to the Anatomical Therapeutic Chemical (ATC) 13 classification system.16 The hospital records include information concerning the primary and 14 secondary diagnoses, procedures, and dates of hospital admission and discharge. All 15 diagnoses are coded according to the ICD-9-CM (International Classification of Diseases, 9th 16 Revision, Clinical Modification). 17 For this study, ethical approval was not relevant because data were anonymized before 18 entering the PHARMO database. 19 20 Patient selection 21 We included patients who in 2003 were dispensed at least two prescriptions of daily used 22 respiratory drugs with ATC-code R03, i.e. inhaled beta-2-agonists, inhaled anticholinergics, 23 inhaled corticosteroids, oral , or a combination of these agents. We included 24 patients aged 50 years or older, in order to exclude patients with uncomplicated . 25 Furthermore, patients using receptor antagonists (LTRAs) (, ATC- 26 code R03DC03) or cromoglycates (R03BC) and patients who had been hospitalised with a

27 diagnosis of asthma (ICD-9-CM) in the previous 2 years or during follow-up were excluded. http://thorax.bmj.com/ 28 The cohort entry date was the date of first dispensing of any R03 drug in 2003. Patients were 29 followed until 31 December 2005. If patients had died before that date, they were censored at 30 the date of death. Apart from age, sex, and respiratory drugs, also data on co-medication for 31 cardiovascular disease and diabetes mellitus, as well as previous hospitalisations for COPD 32 and pneumonia were collected. 33 34 Definition of exacerbation on September 30, 2021 by guest. Protected copyright. 35 To address the study question, we identified those patients who experienced one or more 36 exacerbations. Our assumption is that, in these patients who are on respiratory drugs, a short 37 course of oral corticosteroids is almost exclusively prescribed in case of an exacerbation. 38 Therefore, we defined an exacerbation as a documented dispensing of a short course of oral 39 corticosteroids, with or without antibiotics. We documented the date of dispensing of oral 40 corticosteroids (ATC code: H02AB06/ H02AB07), with or without antibiotics. We scored the 41 antibiotics doxycyclin (ATC-code: J01AA02), amoxicillin (J01CA04), amoxicillin- 42 clavulanate (J01CR02), azithromycin (J01FA10), clarithromycin (J01FA09), ciprofloxacin 43 (J01MA02), moxifloxacin (J01MA14), levofloxacin (J01MA12), and erythromycin 44 (J01FA01), because, in the Netherlands, these cover almost all antibiotics dispensed for 45 exacerbations of COPD.17 We did not include episodes treated only with antibiotics, because 46 information on the coinciding diagnosis was unavailable. 47 As symptoms, increased at the onset of exacerbation, are usually substantially improved after 48 three weeks,18 we presumed that a second prescription for steroids within 3 weeks suggested 49 an exacerbation not well responding to the initial therapy. To avoid counting these 50 prescriptions as a “next exacerbation”, we introduced a minimum interval between steroid

4 Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from 1 courses of three weeks. If the time between two dispensings exceeded three weeks, we 2 considered the second episode as a new exacerbation. As a consequence, until three weeks 3 after the first course was dispensed, patients were considered not to be at risk for a new 4 exacerbation. Patients dispensed oral corticosteroids or antibiotics for more than 21 days at 5 regular intervals, for a period of three months or longer, were excluded from the analysis, 6 because they are likely to be patients on maintenance treatment with oral corticosteroids or 7 antibiotics, respectively. 8 9 Statistical analysis 10 We assessed the first exacerbation after cohort entry (first course of oral corticosteroids) and 11 calculated the time to the second exacerbation (second course of oral corticosteroids). 12 Similarly, we calculated the time between second and the third exacerbation. We compared 13 these time periods between patients treated with oral corticosteroids only, and those treated 14 with oral corticosteroids combined with antibiotics using Kaplan-Meier survival analysis. 15 Patients were censored for exacerbation free survival. The effect of the variable of primary 16 interest, oral corticosteroid (coded as 0) or oral corticosteroid with antibiotic (coded as 1), 17 was analysed in a Cox proportional hazards model. All exacerbations from each patient were 18 used, and time was set back to zero after each exacerbation (gap-time unrestricted model).19 19 Hence, each exacerbation was treated as a separate record and time since last exacerbation as 20 principal time scale. A correction for recurrent exacerbation events from the same individual 21 was made by including a frailty term in the model.20 The Schoenfeld residuals as obtained 22 from the model of time to first exacerbation suggested the difference in treatment effect be 23 highly nonproportional. Therefore, we allowed the difference in treatment effect to change at 24 three months, six months and one year. The data were coded so that hazard ratios below unity 25 indicated a preventive effect of adding an antibiotic to the oral corticosteroids. Potential 26 confounding by the following factors was controlled for: sex, age, number of dispensings of

27 respiratory drugs, including inhaled corticosteroids, co-medication for cardiovascular disease http://thorax.bmj.com/ 28 (yes/no) or for diabetes (yes/no), and previous hospitalisation for COPD and pneumonia 29 (yes/no).21 Dispensing of antibiotics unrelated to exacerbations were also treated as a time- 30 dependent covariate, and assumed to be of influence for a period of three months. This means 31 that three months after dispensing this antibiotic, the variable was again coded as no 32 antibiotic. All-cause mortality of both treatment groups was analyzed using Kaplan-Meier 33 survival analysis and Cox regression analysis. We calculated 99% confidence intervals. 34 Analyses were performed using Stata software, version 9.2 (StataCorp, College Station on September 30, 2021 by guest. Protected copyright. 35 Texas, USA), R-2.6.0 (R Development Core Team (2007). R: A language and environment 36 for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3- 37 900051-07-0, URL http://www.R-project.org.) and SPSS v. 14.0.2 software (SPSS Inc., 38 Chicago, Il, USA). 39

5 Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from 1 Results 2 3 Patients 4 From the PHARMO database we identified 52 753 patients, 50 years and older, fulfilling the 5 prespecified criteria on respiratory drug use. In total, 3114 patients who had been hospitalised 6 with a diagnosis asthma or used LTRAs or cromoglycates were excluded, and 40 patients 7 were excluded because of administrative errors, leaving 49 599 patients. Of these patients, 19 8 882 (40%) had had at least one exacerbation as previously defined. 715 patients were 9 excluded from further analysis because they were likely to be on maintenance treatment with 10 oral corticosteroids (n=349), or with antibiotics (n=366). 239 patients were not at risk for a 11 next exacerbation, as they had only one exacerbation within the three weeks before the end of 12 follow-up, leaving 18 928 patients for further analysis. 13 14 1053 patients (6%) died during the follow-up period. For 894 patients the cause of death was 15 unknown, 159 patients died during hospitalization for COPD. This was counted as an event, 16 and not right-censored. After the first exacerbation, 2341 hospital admissions for COPD 17 occurred; 1636 within one month of a documented exacerbation and 546 independently from 18 a registered exacerbation. These 546 hospital admissions were considered as an event; instead 19 of ‘time to the next exacerbation’, time to hospital admission was counted. As information on 20 in-hospital treatment was not available, they were not analyzed further. 21 22 The median follow-up time after the first exacerbation was 754 days [interquartile range 23 (IQR) 437-974]. In total, 18 928 patients were followed for 36 104 person years. GPs 24 prescribed 72% of all antibiotics, oral corticosteroids and respiratory maintenance 25 medication, 24% came from pulmonologists and 5% from other or unknown prescribers. 26 Antibiotics used in the treatment of first exacerbations were doxycyclin (n=4011, 41%),

27 penicillins (amoxicillin-clavulanate and amoxicillin, n=3597, 37%), macrolides http://thorax.bmj.com/ 28 (azithromycin and clarithromycin, n=1916, 20%), and fluoroquinolones (ciprofloxacin, 29 moxifloxacin and levofloxacin, n=260, 3%). 53 cases could not be assigned to a treatment 30 group. 31 32 Table 1. Characteristics of patients according to treatment of first exacerbation Total Oral Oral corticosteroids p‡ corticosteroids and antibiotics on September 30, 2021 by guest. Protected copyright. n=18 928 n=9 074 n=9 854 Gender Male 9 395 (50) 4 536 (50) 4 859 (49) Female 9 533 (50) 4 538 (50) 4 995 (51) 0.35 Age (years)* 70 (61-77) 70 (61-77) 70 (61-77) 0.60 Number of respiratory dispensings in 2003* 8 (4-13) 8 (4-13)§ 8 (4-13)§ <0.01 ICS§ (maintenance medication) 16 771 (89) 7 883 (87) 8 888 (90) <0.01 Co-medication Cardiovascular 12 995 (69) 6 245 (69) 6 750 (68) 0.63 Diabetes 2 682 (14) 1 264 (14) 1 418 (14) 0.36 Hospitalisation# for COPD† 1 925 (10) 994 (11) 931 (9) <0.01 Pneumonia 651 (3) 325 (4) 326 (3) 0.30 Follow-up characteristics Follow-up time (days)* 754 (437-974) 786 (472-988) 739 (404-957) Number of exacerbations* 2 (1-4) 2 (1-4) 2 (1-3)

6 Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from 1 Data are n (%), unless otherwise stated. *Median (Interquartile range). §ICS: Inhaled corticosteroids. #Once or 2 more in previous 2 years. †Diagnosis: chronic bronchitis, emphysema or chronic obstructive pulmonary disease. 3 ‡Chi-square or Mann-Whitney test, where appropriate. §The oral corticosteroids and antibiotics group had a 4 significant higher number of respiratory dispensings, but the 25th, 50th and 75th percentiles for both treatment 5 groups were similar. 6 7 Kaplan-Meier estimates of the cumulative incidence of developing a second or third 8 exacerbation stratified according to treatment type (oral corticosteroids with or without 9 antibiotics) 10 11 Time to second exacerbation 12 Of 18 928 patients having had at least one exacerbation, the first exacerbation after cohort 13 entry was treated with oral corticosteroids only in 48% (9074 patients) and with oral 14 corticosteroids and antibiotics in 52% (9 854 patients). These two groups of patients were 15 similar with respect to age, gender, use of co-medication for diabetes and cardiovascular 16 disease, and the number of previous hospitalisations for pneumonia. However, more patients 17 in the oral corticosteroids with antibiotics group were dispensed prescriptions of respiratory 18 maintenance drugs and inhaled corticosteroids over time (p<0.01). On the other hand, this 19 group had had fewer hospital admissions for COPD in the previous two years compared to 20 patients in the oral corticosteroids only group (p<0.01) (Table 1). 21 The time to the second exacerbation was much shorter in the oral corticosteroids only group 22 than in the oral corticosteroids with antibiotics group (Figure 1A). The median time between 23 the first and the second exacerbation in the oral corticosteroids only group was 321 days 24 (99% CI 297-345) compared to 418 (99% CI 393-443) days in the oral corticosteroids with 25 antibiotics group. Six months after the first exacerbation, 60% in the oral corticosteroids only 26 group had had no new exacerbation compared to 70% in the oral corticosteroids with 27 antibiotics group. Twelve months after the first exacerbation this was 48% and 54%

28 respectively. There were no differences between antibiotic treatment groups with respect to http://thorax.bmj.com/ 29 time to the second exacerbation. The median time to the second exacerbation was 414 (99% 30 CI 377-451) days for doxycyclin, 415 (371-458) days for penicillins, 431 (376-486) days for 31 macrolides and 329 (189-469) days for fluoroquinolones (p=0.14). 32 33 During follow-up, 472/9854 (4.8%) patients died in the oral corticosteroid and antibiotic 34 group versus 581/9074 (6.4%) in the corticosteroid only group (p<0.01, figure 2). In a 35 univariate Cox regression model the Hazard Ratio (HR) of mortality after treatment with oral on September 30, 2021 by guest. Protected copyright. 36 corticosteroids and antibiotics compared to corticosteroids only was 0.78 (99% CI 0.62– 37 0.94). In a multivariable Cox model, adjusting for potential confounders (sex, age, number of 38 dispensings of respiratory drugs, including inhaled corticosteroids, co-medication for 39 cardiovascular disease or for diabetes, previous hospitalisation for COPD and pneumonia, 40 and exposure to antibiotics unrelated to exacerbation), the HR was 0.82 (99% CI 0.66-0.98). 41 42 Time to third exacerbation 43 Of the 18 928 patients with a first exacerbation, 10 588 had had a second exacerbation. Of 44 these exacerbations, 5420 (51%) were treated with oral corticosteroids and 5168 (49%) with 45 oral corticosteroids and antibiotics. After the second exacerbation the difference between the 46 two treatment groups with respect to the time to the next (third) exacerbation was even more 47 pronounced than after the first exacerbation (Figure 1B). The median time between the 48 second and the third exacerbation was 127 (99% CI 117-137) days in the oral corticosteroids 49 only group and 240 (99% CI 222-258) days in the oral corticosteroids with antibiotics group. 50 Six months after the second exacerbation, 42% of patients treated with oral corticosteroids 51 had not had a third exacerbation compared to 57% of patients treated with oral corticosteroids

7 Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from 1 and antibiotics; after one year this was 30% and 39% respectively. 2 3 Cox recurrent event survival analysis of developing new exacerbations: effect of treatment 4 type 5 In a univariate Cox regression model the Hazard Ratio (HR) of a new exacerbation after 6 treatment with oral corticosteroids and antibiotics compared to corticosteroids only was 0.63 7 (99% CI 0.61–0.66) ) in the first three months following treatment. In a multivariable Cox 8 model adjusting for potential confounders, the HR of a new exacerbation after treatment with 9 corticosteroids with antibiotics was 0.62 (99% CI 0.60-0.65) in the first three months 10 following treatment, but the effect difference decreased in subsequent time periods. Exposure 11 to antibiotics unrelated to exacerbations decreased the risk of a new exacerbation [HR 0.82 12 (99% CI 0.78-0.87)]. Hospitalisation for COPD in the previous two years increased the risk 13 [HR 1.45 (99% CI 1.35-1.57)]. The variables ‘age’ and ‘number of respiratory drugs 14 dispensings in 2003’ were included in the Cox model, but were not fitted linearly, therefore 15 HR are not presented. The risk of a new exacerbation increased with age until 80 years and 16 with a higher number of respiratory drugs dispensings in 2003 up to a number of 50 17 dispensings, but decreased after these values. 18 19 Table 2. Hazard Ratio’s of determinants of developing a next exacerbation after oral 20 corticosteroids with antibiotics - compared to oral corticosteroids only -treatment in a 21 multivariable Cox model Hazard ratio of 99% CI for hazard ratio new exacerbation Lower Upper Antibiotics added to treatment with oral corticosteroids 0-3 months following treatment 0.62 0.60 0.65 3-6 months ,, ,, 0.68 0.65 0.73

6-12 months ,, ,, 1.03 0.96 1.12 http://thorax.bmj.com/ > 12 months ,, ,, 1.31 1.18 1.45 Exposure to antibiotics after previous exacerbation 0.82 0.78 0.87 Female sex 0.95 0.91 1.00 Inhaled corticosteroids as maintenance medication 0.91 0.84 0.98 Co-medication cardiovascular 1.16 1.10 1.23 Co-medication for diabetes 1.05 0.98 1.12 Hospitalisation* for COPD† 1.45 1.35 1.57 on September 30, 2021 by guest. Protected copyright. Hospitalisation for pneumonia 1.19 1.05 1.34 22 CI, Confidence interval. *Once or more in previous 2 years. †Diagnosis: chronic bronchitis, emphysema or 23 chronic obstructive pulmonary disease. The variables ‘age’ and ‘number of respiratory drugs dispensings in 24 2003’ were included in the Cox model, but were not fitted linearly, therefore HR are not presented. 25 26 Checking the assumption that a short course of oral corticosteroids in patients who are on 27 respiratory drugs, is dispensed in case of an exacerbation of COPD. 28 We defined an exacerbation as a course of oral corticosteroids (with or without antibiotics), 29 assuming that (in the Netherlands) a course of oral corticosteroids in this population of 30 patients on maintenance respiratory drugs is almost exclusively prescribed because of an 31 exacerbation of COPD. We checked this assumption by investigating data based on the 32 Second Dutch National Survey of General Practice (DNSGP-2), carried out by The 33 Netherlands Institute for Health Services Research (NIVEL). This registration database gives 34 a representative impression of morbidity and prescribing habits in Dutch general practice.22 35 From 01 January 2002 to 31 December 2002, from 1037 patients with COPD defined 36 according to the international classification of primary care (ICPC) code R95,23 we analysed

8 Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from 1 1355 prescriptions of oral corticosteroids. Twelve hundred and fifty-four prescriptions (92%) 2 were COPD-related. Forty prescriptions (3%; upper limit of the 95% CI: 4.0) were prescribed 3 for ‘other musculoskeletal/connective disorders’ (ICPC-code L99). In addition, sixty-one 4 prescriptions (4%; upper limit of the 95% CI: 5.7) were prescribed for other indications. 5 Extrapolating these findings to the present study, we think our definition of exacerbation was 6 appropriate, and this small percentage of misclassified patients would cause bias towards the 7 null. 8 http://thorax.bmj.com/ on September 30, 2021 by guest. Protected copyright.

9 Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from 1 Discussion 2 3 In this historical follow-up study among 18 928 patients with an exacerbation of obstructive 4 lung disease, and focussing on relapse and not on short-term recovery, we showed that 5 treatment with oral corticosteroids and antibiotics compared to treatment with oral 6 corticosteroids alone was associated with a longer time to the next exacerbation, and a 7 decreased risk of developing a new exacerbation. Exposure to antibiotics between 8 exacerbations was also associated with a lower risk of a subsequent exacerbation. In addition, 9 in the group also treated with antibiotics mortality during follow-up was significantly lower. 10 As in the majority of cases the cause of death was unknown, we are cautious to claim a 11 survival benefit, but this finding is important and certainly warrants confirmation in a 12 prospective study. 13 14 Deriving the data from a pharmacy database enabled us to measure actually dispensed 15 medication in a very large number of patients treated with maintenance treatment for 16 obstructive lung disease. Prescriptions both from general practitioners and pulmonologists 17 were documented. 18 A limitation of observational studies might be the presence of treatment selection bias, due to 19 unknown, potentially prognostic important differences among patients.24 In our study, clinical 20 information on patients was not available. However, patients treated with antibiotics and oral 21 steroids are likely to have more severe exacerbations compared to patients treated with oral 22 steroids only. Therefore, we suspect that any treatment selection bias, if present, would cause 23 bias towards the null, thus underestimating the effect of adding antibiotics. 24 We found the effect of treatment was strongest in the first three months following treatment 25 and then gradually decreased, and even reversed after one year. Apparently the protective 26 effect of antibiotics wanes over time, which is to be expected.

27 Patients could not be selected based on a diagnosis of COPD or chronic bronchitis. Therefore, http://thorax.bmj.com/ 28 we selected patients who used maintenance respiratory drugs used in the treatment of 29 obstructive lung disease. We included patients aged 50 years or older, in order to exclude 30 patients with uncomplicated asthma. Furthermore, we excluded patients who had been 31 hospitalised with a diagnosis of asthma and those using LTRAs or cromoglycates. 32 Nevertheless, a small proportion of patients with asthma may still have been included in this 33 study. 34 on September 30, 2021 by guest. Protected copyright. 35 Recent studies stress the benefits from antibiotic treatment in exacerbations of COPD,25 and a 36 recent Cochrane review reports reduction of mortality and treatment failure, although in 37 community-based studies no differences were found between antibiotic and placebo.4 Most 38 studies so far have been conducted in clinical settings, frequently in hospitalised patients, 39 with merely severe exacerbations. For patients treated in general practice, studies showed no 40 advantage of antimicrobial treatment on short-term outcome.5,6,7 In the population we studied, 41 GPs were responsible for 72% of all dispensings. In general, these COPD patients can be 42 classified as GOLD 2 (moderate COPD).26 So, also in patients with less severe exacerbations, 43 antibiotic treatment added to treatment with oral corticosteroids seems advantageous. The 44 differences we found with respect to time from the first to the second exacerbation and from 45 the second to the third exacerbation, suggest that in patients with frequent exacerbations the 46 benefits of antibiotic treatment added to treatment with oral corticosteroids may be greater. 47 Most randomised trials have follow-up durations of not more than six weeks.27 Benefits from 48 antibiotic treatment may become more apparent in the long-term follow-up compared to 49 short-term evaluations, possibly due to antibiotic treatment decreasing bacterial load. The 50 finding that exposure to antibiotics for any indication also decreased the risk of a next

10 Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from 1 exacerbation may suggest that some COPD patients carrying bacteria in a stable state could 2 benefit from antibiotics. 3 There is sufficient evidence for the contributory role of bacteria in exacerbations. During 4 bacterial exacerbations bacteria are present in the lower airways, associated with airway 5 inflammation, and in sufficient concentrations (>1 000 cfu/mL) to cause invasive 6 infections.28 Inflammatory changes are also related to recurrent exacerbations.29 Immune 7 responses to bacteria play an important role, and especially nontypeable H influenzae is 8 known for its role in the process of colonisation and infection.30-33 Isolation of new strains of 9 bacterial pathogens increases the risk of an exacerbation.34 Increased sputum purulence is the 10 main sign of a new or increased significant bacterial stimulus.25,28,35,36 In addition, patients 11 with severe exacerbations are known to benefit most from antibiotic treatment.1-4 12 13 We showed that treatment with oral corticosteroids and antibiotics compared to treatment 14 with oral corticosteroids alone was associated with a longer time to the next exacerbation, 15 and a decreased risk of developing a new exacerbation. On the other hand, treating all 16 exacerbations with antibiotics will significantly increase overall antibiotic consumption, 17 which might fuel the increasing rates of resistance among respiratory pathogens.37-41 18 Therefore, future prospective studies should explore for which exacerbations with respect to 19 patient profiles and clinical symptoms in particular antibiotics are indicated. http://thorax.bmj.com/ on September 30, 2021 by guest. Protected copyright.

11 Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from 1 Author information 2 Corresponding author: Berendina M Roede, MSc, Academic Medical Centre – University of 3 Amsterdam, Dept. of Internal Med., Div. of Infectious Diseases, Tropical Medicine, and 4 AIDS, Room F4-217, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 5 Phone: +31-20-5664380 Fax: +31-20-6972286 e-mail: [email protected]. 6 7 Author Contributions: Roede had full access to all of the data in the study and takes 8 responsibility for the integrity of the data and the accuracy of the data analysis. 9 Study concept and design: J Prins, Bresser and Bindels. 10 Acquisition of data: Herings. 11 Analysis and interpretation of data: J Prins, Bresser, Bindels, and Roede. 12 Drafting of the manuscript: Roede. 13 Critical revision of the manuscript for important intellectual content: all authors. 14 Statistical analysis: M Prins, ter Riet, Kok, Geskus and Roede. 15 Study supervision: J Prins, Bresser and Bindels. 16 17 Funding/Support: The study was supported by an unrestricted grant from ‘PICASSO for 18 COPD’, an initiative of Pfizer, Boehringer Ingelheim and the research institute Caphri (Care 19 and Public Health Research Institute) from the University of Maastricht, the Netherlands 20 (Project 004). 21 22 Role of the Sponsor: The funding source had no role in design and conduct of the study; 23 collection, management, analysis, and interpretation of the data; and preparation, review, or 24 approval of the manuscript. 25 26 Acknowledgment: We thank NIVEL for their permission to use data from the Second Dutch

27 National Survey of General Practice (DNSGP-2). http://thorax.bmj.com/ 28 29 Competing interests 30 None declared. 31 32 Copyright 33 The corresponding author has the right to grant on behalf of all authors and does grant on 34 behalf of all authors, an exclusive licence (or non exclusive for government employees) on a on September 30, 2021 by guest. Protected copyright. 35 worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article to 36 be published in Thorax editions and any other BMJPG Ltd products to exploit all subsidiary 37 rights, as set out in our licence http://thorax.bmjjournals.com/ifora/licence.pdf. 38 39 Figure legends 40 Figure 1. Kaplan-Meier estimates of the cumulative incidence of developing a second (Fig 41 1A) or third exacerbation (Fig 1B) stratified according to treatment type 42 Figure 2. Kaplan-Meier estimates of the cumulative survival stratified according to treatment 43 type 44 45 46 47 48 49 50

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16 Figure 1. Kaplan-Meier estimates of the cumulative incidence of developing a second (Fig 1A) or third exacerbation (Fig 1B)

stratified according to treatment type

Figure 1A Figure 1B

n = 18 928 n = 10 588

1,0 1,0 Treatment of exacerbation Oral corticosteroids 0,8 0,8 and Antibiotics Oral corticosteroids

0,6 Oral corticosteroids 0,6 and Antibiotics Oral corticosteroids and Antibiotics Cum Survival

Cum Survival 0,4 0,4

Oral corticosteroids

0,2 0,2

Cumulative event-free outcome Oral corticosteroids

0,0 0,0 0 200 400 600 800 1000 1200 0 200 400 600 800 1000 1200

Progression from first exacerbation (days) Progression from second exacerbation (days)

Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from from Downloaded 2008. August 5 on 10.1136/thx.2008.095349 as published first Thorax: http://thorax.bmj.com/ on September 30, 2021 by guest. Protected by copyright. by Protected guest. by 2021 30, September on Thorax: first published as 10.1136/thx.2008.095349 on 5 August 2008. Downloaded from Figure 2. Kaplan-Meier estimates of the cumulative survival stratified according to treatment

type

n = 18 928

1.00

Oral corticosteroids and Antibiotics

0.95 Treatment of exacerbation Oral corticosteroids and Antibiotics Oral corticosteroids

0.90 Oral corticosteroids

0.85 Cumulative event-free outcome outcome event-free Cumulative http://thorax.bmj.com/

0.80 0 200 400 600 800 1000 1200

Progression from first exacerbation (days)

on September 30, 2021 by guest. Protected copyright.