Clinical Review & Education
JAMA Clinical Evidence Synopsis
Prophylactic Antibiotic Therapy in Chronic Obstructive Pulmonary Disease Samantha C. Herath, MBBS, MPhil, FRACP; Phillippa Poole, BSc, MBChB, MD, FRACP
CLINICAL QUESTION Is prophylactic antibiotic treatment associated with fewer exacerbations or improved health-related quality of life (HRQOL) in patients with chronic obstructive pulmonary disease (COPD)? BOTTOM LINE Continuous macrolide antibiotic use for prophylaxis was associated with a
clinically significant reduction in COPD exacerbations. Pulsed antibiotic use was not associated with benefit. Continuous and pulsed antibiotics were associated with improved HRQOL, but this was not clinically significant.
It is unclear whether prophylactic antibiotics are associated with lower rates of exacerbations in patients with chronic obstructive pulmonary disease (COPD).1 Recent randomized clinical trials (RCTs) have addressed this controversial topic. This JAMA Clinical Evidence Synopsis summarizes a Cochrane review2 of 7 RCTs on prophylactic antibiotic use in COPD.
Summary of Findings Of 7 eligible studies, 5 assessed continuous prophylaxis with a macrolide (azithromycin, clarithromycin, or erythromycin over 1 to 12 months). Only 3 were included in the meta-analysis, because 1 study3
Evidence Profile No. of randomized clinical trials: 7 Study years: Conducted, 2000-2010; published, 2001-2011 No. of patients: 3170 Men: 1870 (59%) Women: 1300 (41%) Race/ethnicity: Unavailable Age, mean (SD): 67 years (2.2) Settings: Hospital outpatient clinics Countries: United States, United Kingdom, China, Denmark, Japan Comparison: Prophylactic antibiotic vs placebo in patients with chronic obstructive pulmonary disease Continuous prophylaxis: azithromycin (1 study,5 n = 1142), 250 mg/d for 12 months; clarithromycin (1 study,3 n = 67), 500 mg/d for 3 months; erythromycin (3 studies,4,6,7 n = 254), 250 mg thrice/d for 6 months; 250 mg twice/d for 12 months; 200-400 mg/d treatment for 1 month, observed for 12 months Pulsed prophylaxis: azithromycin (1 study,8 n = 575), 500 mg/d for 3 days, monthly for 36 months; moxifloxacin (1 study,9 n = 1157), 400 mg/d for 5 days, 8 weekly for 48 weeks, then observed for 72 weeks Primary outcomes: Number of exacerbations, 4 studies (n = 2411)5-7,9; health-related quality of life, 2 studies (n = 1928)5,9 Secondary outcomes: Duration of exacerbations; days of disability; frequency/duration of hospital admissions; lung function; all-cause or respiratory-related mortality; drug resistance; adverse effects
did not have data on the number of patients with exacerbations and another4 was unblinded with a high risk of bias. In these 3 studies5-7 (n = 1262), macrolide prophylaxis was associated with a lower incidence of exacerbations over 6 to 12 months (56/100 patients receiving macrolide prophylaxis vs 69/100 patients receiving placebo; odds ratio [OR], 0.55 [95% CI, 0.390.77]). The number needed to treat (NNT) to prevent 1 patient from having an exacerbation was 8 (95% CI, 5-18; Figure). There was an associated reduction in the rate of exacerbations per patient annually with a rate ratio of 0.73 (95% CI, 0.58-0.91).5-7 There was no association of pulsed antibiotic prophylactic therapy with reduced exacerbation rates, but only 1 study addressed this association (47/ 100 patients receiving pulsed antibiotic prophylaxis vs 51/100 patients receiving placebo; OR, 0.87 [95% CI, 0.69 to 1.09] for 48 weeks; Figure). The other study on pulsed antibiotics8 did not have the required data to be included in this meta-analysis because it was an abstract presentation. Both continuous and pulsed antibiotics were associated with an improved HRQOL measured by the St George’s Respiratory Questionnaire in 2 studies5,9 (n = 1962), but this was smaller than the 4-point improvement regarded as clinically significant (mean difference (MD) in SGRQ score, −2.8 to −4 for treatment group vs −0.6 to −2.8 for placebo; total MD of the 2 studies, −1.78 [95% CI, −2.95 to −0.61]). Overall, there was no difference in the number of adverse events between the antibiotic and placebo groups. However, azithromycin was associated with a significant increase in hearing loss,5 and moxifloxacin with a significant increase in gastrointestinal symptoms.9 In the largest continuous study, azithromycin was not associated with an increased incidence of long corrected QT interval (QTc) or tinnitus.5 Development of resistance to antibiotics is another concern. In 1 study,5 patients without any respiratory pathogens identified in the nasopharyngeal swabs at the beginning of the study acquired new organisms during the course of the study with higher rates of azithromycin resistance in the antibiotic treatment group (81%) compared with the placebo group (41%), P < .001. Patients colonized with moxifloxacin-sensitive pseudomonas at initiation of therapy rapidly became resistant to quinolones.9
jama.com
JAMA June 4, 2014 Volume 311, Number 21
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/31/2015
2225
Clinical Review & Education JAMA Clinical Evidence Synopsis
Figure. Association of Prophylactic Antibiotic Therapy With the Incidence of Chronic Obstructive Pulmonary Disease Exacerbations Antibiotic Therapy Study or Subgroup Continuous antibiotics Albert, 2011 He, 2010 Seemungal, 2008 Subtotal Pulsed antibiotics Sethi, 2010 Total
Exacerbations, Total No. of No. Participants
Placebo Exacerbations, Total No. of No. Participants
Favors Antibiotic
Odds Ratio (95% CI)
Favors Placebo
Weight, %
317 9 28 354
558 18 53 629
380 14 42 436
559 18 56 633
0.62 (0.49-0.79) 0.29 (0.07-1.21) 0.37 (0.17-0.84) 0.55 (0.39-0.77)
40.2 5.2 13.5 58.9
269 623
569 1198
295 731
580 1213
0.87 (0.69-1.09) 0.64 (0.45-0.90)
41.1 100.0 0.05
0.2
1.0
5.0
20
Odds Ratio (95% CI)
Source: Data have been adapted with permission from Wiley.2 The size of the data markers indicate the weight of the study. The odds ratio was calculated using a random-effect model.
Discussion
Limitations
Use of continuous macrolide prophylaxis was associated with a clinically significant reduction in COPD exacerbations in older patients with COPD of at least moderate severity (forced expiratory volume in the first second of expiration [FEV1], 1.2 liters [43% predicted]). However, continuous macrolide prophylaxis was not associated with clinically meaningful improvement in quality of life among COPD patients. Although evidence does not suggest a benefit for pulsed prophylactic antibiotic therapy, only a single published trial addressed this question.9 The development of antibiotic resistance in the community with long-term antibiotic use is of concern along with the potential for other antibiotic-specific adverse events. This review supports cautious use of continuous macrolide prophylaxis with close monitoring for patients with frequent infective COPD exacerbations after other standard therapies have been prescribed.
The few studies in this review had varied inclusion criteria and varying documentation of other standard COPD therapy. Antibiotic duration also varied, with the maximum being 12 months for continuous antibiotics and 36 months for pulsed antibiotics. The longterm effect on antibiotic resistance remains unknown.
ARTICLE INFORMATION Author Affiliations: Day Unit, Department of Respiratory Medicine, Montreal Chest Institute, Montreal, Quebec, Canada (Herath); Department of Medicine, The University of Auckland, Auckland, New Zealand (Poole). Corresponding Author: Samantha C. Herath, MBBS, MPhil, FRACP, Day Unit, Department of Respiratory Medicine, Montreal Chest Institute, 3650, Rue St-Urbain, Level 4, Montreal, Quebec, H2X2P4, Canada ([email protected]). Section Editor: Mary McGrae McDermott, MD, Senior Editor. Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Herath reports grant funding from Boehringer Ingelheim outside the submitted work. No other disclosures were reported. Additional Contributions: We thank the staff at the Cochrane Airways Group, especially Emma Welsh, PhD, Chris Cates, MD, Elizabeth Stovold, MA, and Milo Puhan, PhD. None of those acknowledged received compensation for their contributions.
2226
Comparison of Findings With Current Practice Guidelines
Currently there are no established guidelines or recommendations regarding use of antibiotic prophylaxis for COPD. Areas in Need of Future Study
Trials comparing pulsed vs continuous therapy of the same antibiotic would address the relative benefits and harms of each approach.10 Studies should aim to identify characteristics of patients who benefit most from prophylactic antibiotic use and document adverse effects carefully.10
Submissions: We encourage authors to submit papers for consideration as a JAMA Clinical Evidence Synopsis. Please contact Dr McDermott at [email protected]. REFERENCES 1. Staykova T, Black PN, Chacko EE, Poole P. Prophylactic antibiotic therapy for chronic bronchitis. Cochrane Database Syst Rev. 2003; (1):CD004105. 2. Herath SC, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2013;11(11): CD009764. 3. Banerjee D, Khair OA, Honeybourne D. The effect of oral clarithromycin on health status and sputum bacteriology in stable COPD. Respir Med. 2005;99(2):208-215. 4. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. 2001;120(3): 730-733. 5. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-698. 6. He ZY, Ou LM, Zhang JQ, et al. Effect of 6 months of erythromycin treatment on
inflammatory cells in induced sputum and exacerbations in chronic obstructive pulmonary disease. Respiration. 2010;80(6):445-452. 7. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178 (11):1139-1147. 8. Mygind LH, Pedersen C, Vestbo J, et al. A randomised, placebo controlled 3 years study of prophylactic azithromycin in 575 patients with chronic obstructive pulmonary disease. Presented at: European Respiratory Society Annual Congress; September 18-22, 2010; Barcelona, Spain. 9. Sethi S, Jones PW, Theron MS, et al. Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease. Respir Res. 2010;11:10. 10. Uzun S, Djamin R, Kluytmans JAJW, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS) [published online April 16, 2014]. Lancet Respir Med. 2014; doi:10.1016/S2213-2600(14)70019-0.
JAMA June 4, 2014 Volume 311, Number 21
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/31/2015
jama.com
JAMA Clinical Evidence Synopsis
Prophylactic Antibiotic Therapy in Chronic Obstructive Pulmonary Disease Samantha C. Herath, MBBS, MPhil, FRACP; Phillippa Poole, BSc, MBChB, MD, FRACP
CLINICAL QUESTION Is prophylactic antibiotic treatment associated with fewer exacerbations or improved health-related quality of life (HRQOL) in patients with chronic obstructive pulmonary disease (COPD)? BOTTOM LINE Continuous macrolide antibiotic use for prophylaxis was associated with a
clinically significant reduction in COPD exacerbations. Pulsed antibiotic use was not associated with benefit. Continuous and pulsed antibiotics were associated with improved HRQOL, but this was not clinically significant.
It is unclear whether prophylactic antibiotics are associated with lower rates of exacerbations in patients with chronic obstructive pulmonary disease (COPD).1 Recent randomized clinical trials (RCTs) have addressed this controversial topic. This JAMA Clinical Evidence Synopsis summarizes a Cochrane review2 of 7 RCTs on prophylactic antibiotic use in COPD.
Summary of Findings Of 7 eligible studies, 5 assessed continuous prophylaxis with a macrolide (azithromycin, clarithromycin, or erythromycin over 1 to 12 months). Only 3 were included in the meta-analysis, because 1 study3
Evidence Profile No. of randomized clinical trials: 7 Study years: Conducted, 2000-2010; published, 2001-2011 No. of patients: 3170 Men: 1870 (59%) Women: 1300 (41%) Race/ethnicity: Unavailable Age, mean (SD): 67 years (2.2) Settings: Hospital outpatient clinics Countries: United States, United Kingdom, China, Denmark, Japan Comparison: Prophylactic antibiotic vs placebo in patients with chronic obstructive pulmonary disease Continuous prophylaxis: azithromycin (1 study,5 n = 1142), 250 mg/d for 12 months; clarithromycin (1 study,3 n = 67), 500 mg/d for 3 months; erythromycin (3 studies,4,6,7 n = 254), 250 mg thrice/d for 6 months; 250 mg twice/d for 12 months; 200-400 mg/d treatment for 1 month, observed for 12 months Pulsed prophylaxis: azithromycin (1 study,8 n = 575), 500 mg/d for 3 days, monthly for 36 months; moxifloxacin (1 study,9 n = 1157), 400 mg/d for 5 days, 8 weekly for 48 weeks, then observed for 72 weeks Primary outcomes: Number of exacerbations, 4 studies (n = 2411)5-7,9; health-related quality of life, 2 studies (n = 1928)5,9 Secondary outcomes: Duration of exacerbations; days of disability; frequency/duration of hospital admissions; lung function; all-cause or respiratory-related mortality; drug resistance; adverse effects
did not have data on the number of patients with exacerbations and another4 was unblinded with a high risk of bias. In these 3 studies5-7 (n = 1262), macrolide prophylaxis was associated with a lower incidence of exacerbations over 6 to 12 months (56/100 patients receiving macrolide prophylaxis vs 69/100 patients receiving placebo; odds ratio [OR], 0.55 [95% CI, 0.390.77]). The number needed to treat (NNT) to prevent 1 patient from having an exacerbation was 8 (95% CI, 5-18; Figure). There was an associated reduction in the rate of exacerbations per patient annually with a rate ratio of 0.73 (95% CI, 0.58-0.91).5-7 There was no association of pulsed antibiotic prophylactic therapy with reduced exacerbation rates, but only 1 study addressed this association (47/ 100 patients receiving pulsed antibiotic prophylaxis vs 51/100 patients receiving placebo; OR, 0.87 [95% CI, 0.69 to 1.09] for 48 weeks; Figure). The other study on pulsed antibiotics8 did not have the required data to be included in this meta-analysis because it was an abstract presentation. Both continuous and pulsed antibiotics were associated with an improved HRQOL measured by the St George’s Respiratory Questionnaire in 2 studies5,9 (n = 1962), but this was smaller than the 4-point improvement regarded as clinically significant (mean difference (MD) in SGRQ score, −2.8 to −4 for treatment group vs −0.6 to −2.8 for placebo; total MD of the 2 studies, −1.78 [95% CI, −2.95 to −0.61]). Overall, there was no difference in the number of adverse events between the antibiotic and placebo groups. However, azithromycin was associated with a significant increase in hearing loss,5 and moxifloxacin with a significant increase in gastrointestinal symptoms.9 In the largest continuous study, azithromycin was not associated with an increased incidence of long corrected QT interval (QTc) or tinnitus.5 Development of resistance to antibiotics is another concern. In 1 study,5 patients without any respiratory pathogens identified in the nasopharyngeal swabs at the beginning of the study acquired new organisms during the course of the study with higher rates of azithromycin resistance in the antibiotic treatment group (81%) compared with the placebo group (41%), P < .001. Patients colonized with moxifloxacin-sensitive pseudomonas at initiation of therapy rapidly became resistant to quinolones.9
jama.com
JAMA June 4, 2014 Volume 311, Number 21
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/31/2015
2225
Clinical Review & Education JAMA Clinical Evidence Synopsis
Figure. Association of Prophylactic Antibiotic Therapy With the Incidence of Chronic Obstructive Pulmonary Disease Exacerbations Antibiotic Therapy Study or Subgroup Continuous antibiotics Albert, 2011 He, 2010 Seemungal, 2008 Subtotal Pulsed antibiotics Sethi, 2010 Total
Exacerbations, Total No. of No. Participants
Placebo Exacerbations, Total No. of No. Participants
Favors Antibiotic
Odds Ratio (95% CI)
Favors Placebo
Weight, %
317 9 28 354
558 18 53 629
380 14 42 436
559 18 56 633
0.62 (0.49-0.79) 0.29 (0.07-1.21) 0.37 (0.17-0.84) 0.55 (0.39-0.77)
40.2 5.2 13.5 58.9
269 623
569 1198
295 731
580 1213
0.87 (0.69-1.09) 0.64 (0.45-0.90)
41.1 100.0 0.05
0.2
1.0
5.0
20
Odds Ratio (95% CI)
Source: Data have been adapted with permission from Wiley.2 The size of the data markers indicate the weight of the study. The odds ratio was calculated using a random-effect model.
Discussion
Limitations
Use of continuous macrolide prophylaxis was associated with a clinically significant reduction in COPD exacerbations in older patients with COPD of at least moderate severity (forced expiratory volume in the first second of expiration [FEV1], 1.2 liters [43% predicted]). However, continuous macrolide prophylaxis was not associated with clinically meaningful improvement in quality of life among COPD patients. Although evidence does not suggest a benefit for pulsed prophylactic antibiotic therapy, only a single published trial addressed this question.9 The development of antibiotic resistance in the community with long-term antibiotic use is of concern along with the potential for other antibiotic-specific adverse events. This review supports cautious use of continuous macrolide prophylaxis with close monitoring for patients with frequent infective COPD exacerbations after other standard therapies have been prescribed.
The few studies in this review had varied inclusion criteria and varying documentation of other standard COPD therapy. Antibiotic duration also varied, with the maximum being 12 months for continuous antibiotics and 36 months for pulsed antibiotics. The longterm effect on antibiotic resistance remains unknown.
ARTICLE INFORMATION Author Affiliations: Day Unit, Department of Respiratory Medicine, Montreal Chest Institute, Montreal, Quebec, Canada (Herath); Department of Medicine, The University of Auckland, Auckland, New Zealand (Poole). Corresponding Author: Samantha C. Herath, MBBS, MPhil, FRACP, Day Unit, Department of Respiratory Medicine, Montreal Chest Institute, 3650, Rue St-Urbain, Level 4, Montreal, Quebec, H2X2P4, Canada ([email protected]). Section Editor: Mary McGrae McDermott, MD, Senior Editor. Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Herath reports grant funding from Boehringer Ingelheim outside the submitted work. No other disclosures were reported. Additional Contributions: We thank the staff at the Cochrane Airways Group, especially Emma Welsh, PhD, Chris Cates, MD, Elizabeth Stovold, MA, and Milo Puhan, PhD. None of those acknowledged received compensation for their contributions.
2226
Comparison of Findings With Current Practice Guidelines
Currently there are no established guidelines or recommendations regarding use of antibiotic prophylaxis for COPD. Areas in Need of Future Study
Trials comparing pulsed vs continuous therapy of the same antibiotic would address the relative benefits and harms of each approach.10 Studies should aim to identify characteristics of patients who benefit most from prophylactic antibiotic use and document adverse effects carefully.10
Submissions: We encourage authors to submit papers for consideration as a JAMA Clinical Evidence Synopsis. Please contact Dr McDermott at [email protected]. REFERENCES 1. Staykova T, Black PN, Chacko EE, Poole P. Prophylactic antibiotic therapy for chronic bronchitis. Cochrane Database Syst Rev. 2003; (1):CD004105. 2. Herath SC, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2013;11(11): CD009764. 3. Banerjee D, Khair OA, Honeybourne D. The effect of oral clarithromycin on health status and sputum bacteriology in stable COPD. Respir Med. 2005;99(2):208-215. 4. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. 2001;120(3): 730-733. 5. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-698. 6. He ZY, Ou LM, Zhang JQ, et al. Effect of 6 months of erythromycin treatment on
inflammatory cells in induced sputum and exacerbations in chronic obstructive pulmonary disease. Respiration. 2010;80(6):445-452. 7. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178 (11):1139-1147. 8. Mygind LH, Pedersen C, Vestbo J, et al. A randomised, placebo controlled 3 years study of prophylactic azithromycin in 575 patients with chronic obstructive pulmonary disease. Presented at: European Respiratory Society Annual Congress; September 18-22, 2010; Barcelona, Spain. 9. Sethi S, Jones PW, Theron MS, et al. Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease. Respir Res. 2010;11:10. 10. Uzun S, Djamin R, Kluytmans JAJW, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS) [published online April 16, 2014]. Lancet Respir Med. 2014; doi:10.1016/S2213-2600(14)70019-0.
JAMA June 4, 2014 Volume 311, Number 21
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Florida International University Medical Library User on 05/31/2015
jama.com
