Rccm2009060837oc 150.157

Antibiotics in Addition to Systemic Corticosteroids forAcute Exacerbations of Chronic ObstructivePulmonary Disease Johannes M. A. Daniels1, Dominic Snijders1, Casper S. de Graaff1, Fer Vlaspolder2, Henk M. Jansen3,and Wim G. Boersma1 1Department of Pulmonary Diseases and 2Department of Microbiology, Medical Center Alkmaar, Alkmaar; and 3Department of PulmonaryDiseases, Amsterdam Medical Center, University of Amsterdam, Amsterdam, The Netherlands Rationale: The role of antibiotics in acute exacerbations is controver-sial and their efficacy when added to systemic corticosteroids is unknown.
Objectives: We conducted a randomized, placebo-controlled trial to determine the effects of doxycycline in addition to corticosteroids on Although evidence suggests that antibiotics are effective in clinical outcome, microbiological outcome, lung function, and acute exacerbations of chronic obstructive pulmonary dis- systemic inflammation in patients hospitalized with an acute exac- ease, most trials were flawed and performed before systemic erbation of chronic obstructive pulmonary disease.
corticosteroids were recognized as a beneficial treatment.
Methods: Of 223 patients, we enrolled 265 exacerbations defined onthe basis of increased dyspnea and increased sputum volume with orwithout increased sputum purulence. Patients received 200 mg of oral doxycycline or matching placebo for 7 days in addition to This study provides evidence that antibiotics in addition to systemic corticosteroids. Clinical and microbiological response, time systemic corticosteroids have a limited and short-lived effect to treatment failure, lung function, symptom scores, and serumC-reactive protein were assessed.
on clinical outcome and symptoms and no effect on lung Measurements and Main Results: On Day 30, clinical success was similar in intention-to-treat patients (odds ratio, 1.3; 95% confidence in-terval, 0.8 to 2.0) and per-protocol patients. Doxycycline showedsuperiority over placebo in terms of clinical success on Day 10 in of approximately one third of severe exacerbations cannot be intention-to-treat patients (odds ratio, 1.9; 95% confidence interval, identified (4). The role of bacteria in AECOPD is controversial.
1.1 to 3.2), but not in per-protocol patients. Doxycycline was also In about 50% of exacerbations significant amounts of potential superior in terms of clinical cure on Day 10, microbiological outcome, bacterial pathogens can be isolated from protected brush use of open label antibiotics, and symptoms. There was no in- specimens obtained by bronchoscopy (5–7). However, the same teraction between the treatment effect and any of the subgroup pathogens are found in the airways of patients in a stable phase variables (lung function, type of exacerbation, serum C-reactive of the disease (5, 8–11). It is impossible for clinicians to distinguish infection from colonization. Nonetheless, antibiotics Conclusions: Although equivalent to placebo in terms of clinical are widely used to treat patients with AECOPD. Several meta- success on Day 30, doxycycline showed superiority in terms of clinical analyses have confirmed the value of antimicrobial therapy (12– success and clinical cure on Day 10, microbiological success, the use 14). Antibiotics seem to be most effective in patients with of open label antibiotics, and symptoms.
increased dyspnea, increased sputum volume, and increased Clinical trial registered with www.clinicaltrials.gov (NCT00170222).
sputum purulence (15). Unfortunately, the placebo-controlled Keywords: pulmonary disease; chronic obstructive pulmonary disease; trials that investigated the efficacy of antibiotics have important limitations (16–18). Furthermore, these trials were conductedseveral decades ago, before systemic steroids were widely Chronic obstructive pulmonary disease (COPD) constitutes a ma- introduced for the treatment of AECOPD (19–22).
jor health problem (1). Acute exacerbations of COPD (AECOPD) It is unclear whether antibiotics have additional benefits have considerable impact on morbidity, mortality, and quality of when applied in patients with more severe exacerbations that life (2, 3). Common triggers for AECOPD include air pollution are already treated with systemic corticosteroids. Sachs and and viral and/or bacterial infection of the airways, but the cause colleagues (23) suggested that antibiotics were redundant whencorticosteroids were given, irrespective of sputum color orbacterial involvement. However, their sample size was small(n 5 71) and it consisted of both patients with COPD and (Received in original form June 4, 2009; accepted in final form October 29, 2009) patients with asthma. In our opinion, therefore, new placebo- Supported by an unrestricted grant from GlaxoSmithKline (The Netherlands).
The funding source had no part in the study design, conduct, or reporting of the We designed a randomized, double-blind, placebo-controlled trial of doxycycline in addition to systemic corticosteroids for Correspondence and requests for reprints should be addressed to Johannes M. A.
patients hospitalized with an acute exacerbation of COPD. Our Daniels, M.D., Department of Pulmonary Diseases, VU University Medical Center, goal was to assess the effects of doxycycline on clinical and De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E-mail: j.daniels@ microbiological response, symptoms, lung function, and sys- temic inflammation (C-reactive protein). The design of this trial This article has an online supplement, which is accessible from this issue’s table of is unique in that it has incorporated several features that were missing in other placebo-controlled trials: first, concomitant treat- ment, including systemic corticosteroids, was fully standardized.
Originally Published in Press as DOI: 10.1164/rccm.200906-0837OC on October 29, 2009Internet address: www.atsjournals.org Second, radiographic signs of pneumonia and fever were exclusion Daniels, Snijders, de Graaff, et al.: Antibiotic Therapy for Acute Exacerbations of COPD criteria to prevent enrollment of patients with pneumonia.
placebo group and 67% for the antibiotic group (type 1 and type 2 Finally, sputum samples were collected before and after the AECOPD combined). We calculated that 167 exacerbations were intervention to allow a thorough microbiological workup. Some needed in both arms to detect the previously mentioned difference of the results of these studies have been previously reported in between antibiotic and placebo treatment on Day 30 with a power of80% and a two-sided a level of 0.05. During the trial we discovered that the percentage of type 1 exacerbations in our trial was higher thanexpected. Therefore we expected a higher treatment effect (16.7%).
Recalculation of the sample size showed that 132 exacerbations wereneeded in each arm.
SPSS 16.0 for Windows (SPSS Inc, Chicago, IL) and Stata version Participants were enrolled at the Medical Centre Alkmaar in Alkmaar, 11.0 (StataCorp, College Station, TX) were used for data management the Netherlands and the Waterland Hospital in Purmerend, the Nether- and statistical analysis. Differences between the treatment groups were lands. The study population consisted of patients 45 years of age or older, analyzed by logistic regression analysis, correcting for within-patient diagnosed with COPD stages I–IV as defined by the Global Initiative clustering with generalized estimating equations. Differences in time to for Chronic Obstructive Lung Disease (GOLD) (25), with an acute treatment failure were compared by Cox proportional hazards re- (onset < 14 d) exacerbation (as defined by Anthonisen and colleagues gression, adjusting for within-patient clustering by robust standard [15]: type 1 [increased dyspnea, sputum volume, and sputum purulence] error estimation. Subgroups were specified according to type of exac- or type 2 [two of three symptoms]) that required hospitalization. Criteria erbation, bacterial presence, serum CRP, and lung function. Heteroge- for hospital admission are described in the online supplement. The most neity of treatment effect between subgroups was examined by logistic important exclusion criteria included fever (>38.58C) to prevent enroll- regression analysis. A significance level of 0.05 was specified for all ment of patients with pneumonia, antibiotic treatment for at least comparisons. We did not correct for multiple comparisons because 24 hours, and radiographic signs of pneumonia (not specified). All several sets of end points are closely related and do not represent exclusion criteria are listed in the online supplement.
One planned interim analysis, regarding the primary end point and mortality, that was performed by an independent statistician after Within 24 hours of admission, patients were randomly assigned to enrollment of 140 exacerbations showed no significant differences and receive a 7-day course of doxycycline or placebo. Details about the the study was therefore continued as planned.
randomization process and allocation concealment are presented in theonline supplement. Concomitant treatment consisted of intravenously administered prednisolone (starting with 60 mg/d, tapering by 10 mgper 2 d to 40 mg/d followed by 30 mg of oral prednisolone on Day 7, tapering by 5 mg per 2 d to 0 mg or the maintenance dose before Of the 367 exacerbations that were screened, 265 exacerbations admission), nebulized bronchodilator therapy four to six times daily, of 223 patients were enrolled and randomly assigned to placebo and physiotherapy. Other COPD medication was continued, except forshort-acting bronchodilators. Because all patients received 6 days of (137 exacerbations) or doxycycline (128 exacerbations). After two intravenous steroids the minimum length of stay was 7 days.
enrollments, inclusion at the Waterland Ziekenhuis in Purmerend Throughout the trial, attending physicians were unable to access the was terminated for logistical reasons. The majority of the patients results of sputum cultures. However, when a pathogen was isolated that in the placebo group (110 of 137 [80%]) and the doxycycline is usually resistant to doxycycline, the attending physician was in- group (111 of 128 [87%]) completed the trial (Figure 1). The most formed. In case of clinical treatment failure the attending physician was common reason for withdrawal was lack of efficacy, which was allowed to access the culture results and to replace the study drug by an more common in the placebo group (23 of 137 [17%]) than in the open label antibiotic. Rerandomization was allowed if a new exacer- doxycycline group (8 of 128 [6%]). The baseline characteristics bation occurred at least 3 months after the first enrollment. Safety was are shown in Table 1. Of the 265 enrolled exacerbations, 178 monitored daily with the help of adverse event reports.
(67%) were type 1 and 87 (33%) were type 2.
On Days 1, 10, and 30, patients were assessed clinically: blood sampleswere drawn for measurement of C-reactive protein (CRP, Beckman On Day 30, clinical success was observed in 78 patients (61%) Coulter Inc., Fullerton, CA) and serologic testing, spirometry was from the doxycycline group and 72 patients (53%) from the performed and expectorated sputum samples were collected. Symptom placebo group (odds ratio [OR], 1.3; 95% confidence interval scores consisted of visual analog scales (VAS) for dyspnea, cough, [95% CI], 0.8 to 2.0; P 5 0.32) (Table 2). In the per-protocol fatigue, and sputum purulence. For each symptom the minimal score population we found similar results (OR, 1.2; 95% CI, 0.7 to 1.9; was 1 and the maximal score was 10. Separate and total scores were calculated. Microbiological procedures are described in detail in theonline supplement.
The primary end point was clinical response on Day 30 as defined by Chow and colleagues (26) Treatment success was defined as cure (a Clinical outcome on Day 10. On Day 10, clinical success was complete resolution of signs and symptoms associated with the exacer- observed in 103 patients (80%) from the doxycycline group and bation) or improvement (a resolution or reduction of the symptoms and 94 patients (69%) from the placebo group (OR, 1.9; 95% CI, 1.1 signs without new symptoms or signs associated with the infection).
to 3.2; P 5 0.03). This significant difference was lost in the per- Treatment failure was defined as absence of resolution of symptoms and protocol population (OR, 1.8; 95% CI, 1.0 to 3.1; P 5 0.05).
signs, worsening of symptoms and signs, occurrence of new symptoms Clinical cure. Clinical cure was observed in 86 patients and signs associated with the primary or a new infection or death.
(67%) from the doxycycline group and 69 patients (51%) from Secondary end points included clinical success on Day 10, clinical cure the placebo group on Day 10 (OR, 1.9; 95% CI, 1.2 to 3.2; P 5 on Days 10 and 30, antibiotic treatment for lack of efficacy, lung function(DFEV 0.01). On Day 30 clinical cure was observed in 65 patients 1), time to treatment failure (defined previously), serum C-reactive protein (CRP), symptoms, and microbiological response. Criteria for (51%) from the doxycycline group and 56 patients (41%) from microbiological response are described in the online supplement.
the placebo group (OR, 1.4; 95% CI, 0.9 to 2.3; P 5 0.15).
Time to treatment failure. Time to treatment failure (defined as absence of resolution of symptoms and signs, worsening of Our sample size calculation was based on the results of Anthonisen and symptoms and signs, occurrence of new symptoms and signs colleagues (15), who found a clinical success rate of 52% for the associated with the primary or a new infection or death) was not AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Figure 1. Enrollment and fol-low-up of patients. Shows thescreening, dom assignment, and follow-up of patients.
significantly longer in the doxycycline group than in the placebo 238.9 6 72.7 mg/L in the placebo group (P 5 0.07) (Table 2).
group (P 5 0.19 by the log-rank test) (Figure 2). Forty-six This trend was no longer present on Day 30.
patients (37%) in the doxycycline group and 62 patients (46%) Symptom scores. The mean change in total symptoms score in the placebo group had treatment failure.
on Day 10 was 210.1 6 9.0 in the doxycycline group and 26.2 6 Antibiotic treatment for lack of efficacy. Open label antibiotic 8.6 in the placebo group (mean difference, 22.3; 95% CI, 23.9 treatment for lack of efficacy was applied in 19 patients (15%) to 20.8; P 5 0.003) (Table 2). On Day 30, the mean change was of the doxycycline group and 38 patients (28%) in the placebo 29.4 6 9.7 in the doxycycline group and 28.3 6 8.6 in the group by Day 10 (OR, 0.5; 95% CI, 0.3 to 0.9; P 5 0.01) and 42 placebo group (mean difference, 21.0; 95% CI, 23.7 to 1.8; P 5 patients (33%) in the doxycycline group and 61 patients (45%) 0.50). Separate mean symptom scores of cough and sputum of the placebo group by Day 30 (OR, 0.7; 95% CI, 0.4 to 1.1; purulence were significantly more reduced in those treated with doxycycline on Day 10, but not on Day 30 (Table 2).
Lung function. Paired lung function data were available for Microbiological outcome. Two hundred and fourteen poten- 224 patients (85%) on Days 1 and 10 and in 189 patients (71%) tial bacterial pathogens were isolated in 158 exacerbations. The on Days 1 and 30. The mean increase in FEV1 on Day 10 was most predominant bacteria were Haemophilus influenzae 0.16 6 0.26 L in the doxycycline group and 0.11 6 0.26 L in the (41%), Streptococcus pneumoniae (24%) and Moraxella catar- placebo group (mean difference, 0.05 L; 95% CI, –0.02 to 0.12; rhalis (22%). A viral infection was serologically diagnosed in P 5 0.16) (Table 2). On Day 30, the mean increase was 0.15 6 20 patients (influenza A virus, n 5 6; parainfluenza virus, n 5 5; 0.33 L in the doxycycline group and 0.08 6 0.25 L in the placebo respiratory syncytial virus, n 5 5; adenovirus, n 5 3; influenza B group (mean difference, 0.07 L; 95% CI, 20.03 to 0.13; P 5 virus, n 5 1). Resistance to tetracycline was observed in 1% of H. influenzae isolates, 7% of S. pneumoniae isolates, 7% of Serum C-reactive protein. The mean change in serum CRP M. catarrhalis isolates, 0% of Staphylococcus aureus isolates, on Day 10 was 256.4 6 65.5 mg/L in the doxycycline group and and 48% of Pseudomonas spp. isolates. We were able to evaluate Daniels, Snijders, de Graaff, et al.: Antibiotic Therapy for Acute Exacerbations of COPD TABLE 1. BASELINE PATIENT CHARACTERISTICS Definition of abbreviations: AECOPD 5 acute exacerbation of COPD; FEV1 5 postbronchodilator forced expiratory volume in 1 second; ICS 5 inhalation corticosteroids; IQR 5 interquartile range; SCS 5 systemic corticosteroids.
Plus–minus values represent means 6 SD.
* The body mass index is the weight in kilograms divided by the square of the height in meters.
† Last recorded postbronchodilator value in a stable state before admission.
the bacteriological response in 151 patients (Table 3). In the doxycycline group bacteriological success was accomplished in52 of 78 patients (67%) and in the placebo group in 25 of 73 We found no significant difference in clinical outcome on Day 30 patients (34%) (OR, 3.8; 95% CI, 1.9 to 7.5; P among patients with AECOPD who were randomly assigned to 3). For the three most predominant pathogens (H. influenzae, doxycycline as compared with those who were assigned to S. pneumoniae, and M. catarrhalis) the success rates were placebo. Doxycycline was superior to placebo in terms of clinical significantly better in the doxycycline group (Table 3). In the success and clinical cure on Day 10 as well as microbiological doxycycline group bacterial persistence rates were 31% for H.
success. In addition, open label antibiotic therapy for lack of influenzae, 17% for S. pneumoniae, and 9% for M. catarrhalis.
efficacy occurred significantly less often in patients assigned todoxycycline. Finally, patients taking doxycycline had a greater reduction in symptoms on Day 10. We did not see a difference inrecovery of lung function, resolution of systemic inflammation, On Day 10 doxycycline showed superiority in patients with type and time to treatment failure between the treatment groups.
1 AECOPD and patients with a CRP value of 50 mg/L or more This is the first placebo-controlled trial of antibiotics in (Figure 3a). However, the treatment effect did not differ among addition to systemic corticosteroids for acute exacerbations of these subgroups. On Day 30 doxycycline was still superior to COPD. We did not find a significant treatment effect at the placebo in patients with a CRP of at least 50 mg/L, but not in primary end point (clinical success on Day 30). This observation patients with type 1 AECOPD (Figure 3B). Again, no in- could be explained by several factors: first, systemic steroids teraction between the treatment effect and any of the subgroup have proven to be highly beneficial in hospitalized patients (19– 22). The benefit of antibiotics on top of systemic steroids mightbe smaller than that observed in other studies where systemic steroids were often withheld or applied only in a minority of Adverse reactions that were considered to be related to the patients. Second, we excluded patients with fever and patients study medication occurred in four patients (3%) in the doxy- with chest radiographs suggestive of pneumonia. This was not cycline group and five patients (4%) in the placebo group.
done in other placebo-controlled trials. Consequential enroll- Adverse reactions in both groups were heartburn, diarrhea, and ment of patients with pneumonia might have inflated the nausea. All reactions were mild and self-limiting. In only one observed treatment effects. Third, we studied patients with patient was the study medication discontinued, because of an moderate to severe COPD with exacerbations that required adverse reaction (placebo group, complaints of heartburn).
hospitalization. The severe nature of these exacerbations might Serious adverse events occurred in 11 patients (9%) from the have caused a large proportion to relapse early, thereby doxycycline group (11 events, including 7 deaths) and 7 patients attenuating the treatment effect. A fourth explanation could (5%) from the placebo group (7 events, including 3 deaths).
be insufficient antibacterial activity of doxycycline. Tetracy- Serious adverse events in the doxycycline group included clines were used in the majority of placebo-controlled trials so pneumonia, urinary tract infection, myocardial infarction, and far and the resistance rates of the commonly isolated bacterial hypoglycemia. One patient died of gram-negative sepsis, four pathogens in our region are low. Nonetheless, although persis- patients died of respiratory failure, and two patients died of tence rates for S. pneumoniae and M. catarrhalis were low, we acute heart failure. Serious adverse events in the placebo group did prove persistence in 31% of patients with H. influenzae who included pneumonia and stomach perforation. One patient died received doxycycline whereas the in vitro resistance rate of of pneumonia and two died of respiratory failure.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE TABLE 2. EFFECTS OF INTERVENTION ON PRIMARY AND SECONDARY END POINTS IN THE INTENTION-TO-TREAT POPULATION Open-label antibiotic treatment for lack of efficacy, no. (%) Definition of abbreviations: 95% CI 5 95% confidence interval; CRP 5 C-reactive protein.
Values are listed as mean 6 SD unless stated otherwise.
* Corrected for within-patient clustering.
† Symptoms scores were assessed with a visual analog scale (scale 1–10).
Persistence of H. influenzae strains after antibiotic therapy, 0.14). We therefore cannot claim interaction between the even if the strain is susceptible to the prescribed antibiotic, is treatment effect of doxycycline and the type of exacerbation.
a well-known phenomenon (27, 28). An in vitro study showed Because sputum purulence is a marker for bacterial infection, that penetration of H. influenzae between epithelial cells pro-tects the bacteria from antibody-mediated defense mechanismsand antibiotics (29). There is sufficient evidence to suggest thatfluoroquinolones such as moxifloxacin outperform conventionalantibiotics in terms of bacterial eradication, especially of H.
influenzae. In spite of this there is no evidence of clinical supe-riority over conventional antibiotics and only limited evidenceof superiority in long-term outcomes such as time to the nextexacerbation (30). In light of this evidence, it seems unjustified toadvocate the use of quinolones for AECOPD in regions withacceptable resistance rates to conventional antibiotics.
As doxycycline was not superior to placebo in the overall analysis, it is important to assess whether certain subgroupsbenefit from antibiotics. An important finding of Anthonisenand colleagues (15) was that antibiotics are most effective inpatients with increased sputum purulence (type 1 AECOPD).
In the current study, we found that doxycycline was superior onDay 10 in patients with a type 1 exacerbation and equivalent in Figure 2. Kaplan-Meier curves showing the effect of the intervention patients with a type 2 exacerbation. The treatment effect, how- on time to treatment failure in the intention-to-treat population.
ever, did not differ significantly between these groups (P 5 *Corrected for within-patient clustering.
Daniels, Snijders, de Graaff, et al.: Antibiotic Therapy for Acute Exacerbations of COPD TABLE 3. BACTERIOLOGICAL RESPONSE ON DAY 10 IN SUBJECTS FROM THE INTENTION-TO-TREATPOPULATION WITH BACTERIAL INFECTION A potential pathogen was identified in 158 exacerbations. The bacteriological response could be evaluated in 151 * Corrected for within-patient clustering.
† Serologic tests were used for the diagnosis of M. pneumoniae and C. pneumoniae infection.
we also established subgroups according to the presence of AECOPD does not necessarily represent a new infection that a bacterial pathogen in expectorated sputum. Again, we found warrants treatment with antibiotics. It is evident that the no interaction with the treatment effect. This finding suggests airways of patients with COPD are often colonized with bac- that the presence of bacteria in the sputum of patients with teria and that increase in bacterial load or even acquisition of a on (A) Day 10 and (B) Day30. Shown are treatment ef-fect (solid squares), 95% confi-dence lines), P values, and P valuesfor interaction between thetreatment effect and the sub-group variable. *Type of exac-erbation was defined accordingto Anthonisen and colleagues(15); †the cutoff value wasprespecified at 10 mg/L. In-creasing clearly altered the results, withthe best results at 50 mg/L;‡predicted FEV1% 5 postbron-chodilator forced expiratoryvolume in 1 second, % ofpredicted (last recorded valuein a stable state before admis-sion). The cutoff value of pre-dicted FEV1% was prespecifiedat 50%. Lowering the cutoffvalue did not alter the results.
AECOPD 5 acute exacerba-tion of COPD; xcorrected forwithin-patient clustering.
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