Where is the supporting evidence for treating mild to moderate chronic obstructive pulmonary disease exacerbations with antibiotics? A systematic review
Open accessAbstract
BACKGROUND: Randomised trials comparing different drugs head-to-head are extremely valuable for clinical decision-making. However, it is scientifically and ethically sensible to demand strong evidence that a drug is effective by showing superiority over a placebo before embarking on head-to-head comparisons of potentially ineffective drugs. Our aim was to study the evolvement of evidence from placebo-controlled and head-to-head trials on the effects of antibiotics for the treatment of mild to moderate exacerbations of chronic obstructive pulmonary disease. METHODS: We conducted a historical systematic review. Through electronic databases and hand-searches, we identified placebo-controlled and head-to-head antibiotic trials for the treatment of mild to moderate chronic obstructive pulmonary disease exacerbations. We compared the numbers of patients recruited in placebo-controlled and head-to-head trials between 1957 and 2005. Using cumulative meta-analysis of placebo-controlled trials, we determined when, if ever, placebo-controlled trials had shown convincing evidence that antibiotics are effective in preventing treatment failure in patients with mild to moderate chronic obstructive pulmonary disease exacerbations. RESULTS: The first head-to-head trial was published in 1963. It was followed by another 100 trials comparing different antibiotics in a total of 34,029 patients with mild to moderate chronic obstructive pulmonary disease exacerbations. Over time, the cumulative odds ratio in placebo-controlled trials remained inconclusive throughout with odds ratios ranging from 0.39 (95% confidence intervals 0.04-4.22) to the most recent estimate (1995) of 0.81 (95% confidence intervals 0.52-1.28, P = 0.37). CONCLUSION: Placebo-controlled trials do not support the use of antibiotics in chronic obstructive pulmonary disease patients with mild to moderate exacerbations. Conducting head-to-head trials is, therefore, scientifically and ethically questionable. This underscores the requirement to perform or study systematic reviews of placebo-controlled trials before conducting head-to-head trials.
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Failure to review the cumulative evidence can lead to trial participants being deprived of effective interventions or exposed to harmful interventions.
“or to trial participants being deprived of effective interventions or exposed to harmful interventions.144 149 150 151”
From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [150]
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2 retracted
Antibiotics for exacerbations of chronic obstructive pulmonary disease
Ram, F. S., Rodriguez-Roisín, R., Granados-Navarrete, A., et al. (2006) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd004403.pub2 · Cited by 170 · see citing works
RetractedProphylactic antibiotic therapy for chronic bronchitis
Staykova, T., Black, P., Chacko, E., & Poole, P. (2001) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd004105 · Cited by 86 · see citing works
Retracted(2014) · The Journal of the American College of Dentists · doi:10.5124/jkma.2014.57.11.899 · Cited by 16,387 · see citing works
Cook, R. J., Dickens, B. M., & Fathalla, M. F. (2003) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780199241323.003.0025 · Cited by 10,813 · see citing works
Antibiotic Therapy in Exacerbations of Chronic Obstructive Pulmonary Disease
Anthonisen, N. R., MANFREDA, J., WARREN, C. P. W., HERSHFIELD, E. S., HARDING, G. K. M., & NELSON, N. A. (1987) · Annals of Internal Medicine · doi:10.7326/0003-4819-106-2-196 · Cited by 2,474 · see citing works
Available, N. (2000) · JAMA · doi:10.1001/jama.284.23.3043 · Cited by 2,344 · see citing works
Tunis (2003) · doi:10.1001/jama.290.12.1624 · Cited by 1,724 · see citing works
Explanatory and Pragmatic Attitudes in Therapeutical Trials
Schwartz, D., & Lellouch, J. (2009) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2009.01.012 · Cited by 1,253 · see citing works
Explanatory and pragmatic attitudes in therapeutical trials
Schwartz, D., & Lellouch, J. (1967) · Journal of Chronic Diseases · doi:10.1016/0021-9681(67)90041-0 · Cited by 1,185 · see citing works
Exercise therapy for treatment of non-specific low back pain
Hayden, J., van Tulder, M. W., Malmivaara, A., & Koes, B. W. (2005) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd000335.pub2 · Cited by 879 · see citing works
Antibiotics for acute otitis media in children
Venekamp, R. P., Sanders, S., Glasziou, P., Mar, C. D., & Rovers, M. M. (2013) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd000219.pub4 · Cited by 619 · see citing works
Antibiotics for exacerbations of chronic obstructive pulmonary disease
Vollenweider, D. J., Jarrett, H., Steurer-Stey, C. A., García‐Aymerich, J., & Puhan, M. A. (2012) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd010257 · Cited by 446 · see citing works
Self-citationAntidepressants for depressed elderly
Mottram, P. G., Wilson, K., & Strobl, J. (2006) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd003491.pub2 · Cited by 289 · see citing works
Mullie, A., Verstringe, P., Buylaert, W. A., Houbrechts, H., Michem, N., Delooz, H. H., Verbruggen, H. W., den Broeck, L. V., Corne, L., & Lauwaert, D. (1988) · PubMed · Cited by 257 · see citing works
Antibiotics for acute otitis media in children
Sanders, S., Glasziou, P., Mar, C. D., & Rovers, M. M. (2004) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd000219.pub2 · Cited by 194 · see citing works
Antidepressants versus placebo for the depressed elderly
Wilson, K., Mottram, P. G., Sivananthan, A., & Nightingale, A. L. (2001) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd000561 · Cited by 180 · see citing works
Fergusson, D. A., Glass, K. C., Hutton, B., & Shapiro, S. (2005) · Clinical Trials · doi:10.1191/1740774505cn085oa · Cited by 165 · see citing works
Bacteria in Exacerbations of Chronic Obstructive Pulmonary Disease: Phenomenon or Epiphenomenon?
Sethi, S. (2004) · Proceedings of the American Thoracic Society · doi:10.1513/pats.2306029 · Cited by 151 · see citing works
Clarke, M. J., Hopewell, S., & Chalmers, L. (2007) · Journal of the Royal Society of Medicine · doi:10.1177/014107680710011415 · Cited by 145 · see citing works
Short-course antibiotics for acute otitis media
Kozyrskyj, A. L., Klassen, T. P., MOFFATT, M. E. K., & Harvey, K. (2010) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001095.pub2 · Cited by 129 · see citing works
Sachs, A. P. E., Koëter, G. H., Groenier, K. H., van der Waaij, D., Schiphuis, J., & Jong, B. M. (1995) · Thorax · doi:10.1136/thx.50.7.758 · Cited by 128 · see citing works
Prophylactic Use of Oxytetracycline for Exacerbations of Chronic Bronchitis
Elmes, P. C., Fletcher, C. M., & Dutton, A. A. C. (1957) · BMJ · doi:10.1136/bmj.2.5056.1272 · Cited by 115 · see citing works
Straus, S. E. (2000) · JAMA · doi:10.1001/jama.283.14.1853 · Cited by 102 · see citing works
Value of ampicillin in the hospital treatment of exacerbations of chronic bronchitis.
Elmes, P. C., King, T. K., Langlands, J. H. M., Mackay, J. A., Wallace, W. F. M., Wade, O. L., & Wilson, T. S. (1965) · BMJ · doi:10.1136/bmj.2.5467.904 · Cited by 96 · see citing works
Update on unethical use of placebos in randomised trials
Michels, K. B., & Rothman, K. J. (2003) · Bioethics · doi:10.1111/1467-8519.00332 · Cited by 84 · see citing works
Puhan, M. A., Vollenweider, D. J., Latshang, T. D., Steurer, J., & Steurer-Stey, C. A. (2007) · Respiratory Research · doi:10.1186/1465-9921-8-30 · Cited by 80 · see citing works
Self-citationScientific and Ethical Issues in Equivalence Trials
Djulbegović, B. (2001) · JAMA · doi:10.1001/jama.285.9.1206 · Cited by 79 · see citing works
Jørgensen, A. F., Coolidge, J. A. S., Pedersen, P. A., Petersen, K. P., Waldorff, S., & Widding, E. (1992) · Scandinavian Journal of Primary Health Care · doi:10.3109/02813439209014027 · Cited by 78 · see citing works
EXACERBATIONS OF CHRONIC BRONCHITIS TREATMENT WITH OXYTETRACYCLINE
Berry, D. G., Fry, J., Hindley, C. P., Hodson, J. M., Horder, E. J., Horder, J., Marien, E. A. W., Rea, J. N., Ryle, A., Curwen, M. P., et al. (1960) · The Lancet · doi:10.1016/s0140-6736(60)90056-8 · Cited by 75 · see citing works
Clarke, M., Hopewell, S., & Chalmers, L. (2007) · Journal of the Royal Society of Medicine · doi:10.1258/jrsm.100.4.187 · Cited by 59 · see citing works
Short-course antibiotics for acute otitis media
Kozyrskyj, A. L., Klassen, T. P., MOFFATT, M. E. K., & Harvey, K. (2000) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001095 · Cited by 44 · see citing works
Antibiotic regimes in chronic bronchitis
Fear, E. C., & Edwards, G. F. (1962) · British Journal of Diseases of the Chest · doi:10.1016/s0007-0971(62)80012-6 · Cited by 42 · see citing works
Fogarty, C. M., de Wet, R., Mandell, L. A., Chang, J. R., Rangaraju, M., & Nusrat, R. (2005) · CHEST Journal · doi:10.1378/chest.128.4.1980 · Cited by 26 · see citing works
Willey, R. F., Gould, J. C., & Grant, I. W. B. (1978) · British Journal of Diseases of the Chest · doi:10.1016/0007-0971(78)90003-7 · Cited by 20 · see citing works
Puhan, M. A., Vollenweider, D. J., Latshang, T. D., Steurer, J., & Steurer-Stey, C. A. (2008) · Respiratory Research · doi:10.1186/1465-9921-9-81 · Cited by 11 · see citing works
Self-citation[Comparison of sulfonamide and penicillin treatment of acute exacerbations in chronic bronchitis].
Christiansen, I. S., & Midtgaard, K. (1963) · PubMed · Cited by 4 · see citing works
Burrow, G. R. F., Fox, A. S., & Daniel, R.-M. (1975) · Journal of International Medical Research · doi:10.1177/030006057500300503 · Cited by 4 · see citing works
Lomefloxacin vs Amoxicillin in Patients with Acute Exacerbations of Chronic Bronchitis
Hamilton, B. A., O'Bryan-Tear, C. G., & Markanday, S. (1993) · Drugs · doi:10.2165/00003495-199300453-00178 · Cited by 3 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- ICH Steering Committee Harmonised tripartite guideline: choice of control group and related issues in clinical trials (E10) International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use: Geneva 2000
- Allegra LG Grassi C Grossi E Pozzi E Blasi F Frigerio D Nastri A Montanari C Montanari M Serra G The role of antibiotics in the treatment of chronic bronchitis exacerbation: follow-up of a multicenter study Ital J Chest Dis 1991 45 138 148 <Author: Please check the title of the journal>
Cited by
Sorted by citations
SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials
Chan, A.-W., Tetzlaff, J. M., Gotzsche, P. C., Altman, D. G., Mann, H., Berlin, J. A., Dickersin, K., Hrobjartsson, A., Schulz, K. F., Parulekar, W. R., et al. (2013) · BMJ · doi:10.1136/bmj.e7586 · Cited by 6,251 · see citing works
Bafadhel, M., McKenna, S., Terry, S., Mistry, V., Reid, C., Haldar, P., McCormick, M. J., Haldar, K., Kebadze, T., Duvoix, A., et al. (2011) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201104-0597oc · Cited by 1,098 · see citing works
Bafadhel, M., McKenna, S., Terry, S., Mistry, V., Pancholi, M., Venge, P., Lomas, D. A., Barer, M. R., Johnston, S. L., Pavord, I. D., et al. (2012) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201108-1553oc · Cited by 611 · see citing works
Antibiotics for exacerbations of chronic obstructive pulmonary disease
Vollenweider, D. J., Jarrett, H., Steurer-Stey, C. A., García‐Aymerich, J., & Puhan, M. A. (2012) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd010257 · Cited by 446 · see citing works
Self-citationLinks Between Inflammatory Bowel Disease and Chronic Obstructive Pulmonary Disease
Raftery, A. L., Tsantikos, E., Harris, N. L., & Hibbs, M. L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.02144 · Cited by 178 · see citing works
SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials
Hróbjartsson, A., Boutron, I., Hopewell, S., Moher, D., Schulz, K. F., Collins, G. S., Tunn, R., Aggarwal, R., Berkwits, M., Berlin, J. A., et al. (2025) · BMJ · doi:10.1136/bmj-2024-081660 · Cited by 171 · see citing works
Llor, C., Moragas, A., Hernandez, S. F., Bayona, C., & Miravitlles, M. (2012) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201206-0996oc · Cited by 151 · see citing works
Clarke, M., Brice, A., & Chalmers, I. (2014) · PLoS ONE · doi:10.1371/journal.pone.0102670 · Cited by 120 · see citing works
Antibiotics for exacerbations of chronic obstructive pulmonary disease
Vollenweider, D. J., Frei, A. L., Steurer-Stey, C. A., García‐Aymerich, J., & Puhan, M. A. (2018) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd010257.pub2 · Cited by 126 · see citing works
Self-citationMiravitlles, M., Moragas, A., Hernandez, S. F., Bayona, C., & Llor, C. (2013) · CHEST Journal · doi:10.1378/chest.13-0518 · Cited by 91 · see citing works
Guidelines for randomized clinical trial protocol content: a systematic review
Tetzlaff, J., Chan, A., Kitchen, J., Sampson, M., Tricco, A. C., & Moher, D. (2012) · Systematic Reviews · doi:10.1186/2046-4053-1-43 · Cited by 80 · see citing works
Hypoxia‐inducible factor and bacterial infections in chronic obstructive pulmonary disease
Shukla, S. D., Walters, E. H., Simpson, J. L., Keely, S., Wark, P. A. B., O’Toole, R., & Hansbro, P. M. (2019) · Respirology · doi:10.1111/resp.13722 · Cited by 79 · see citing works
Hurst, J. R., & Wedzicha, J. A. (2009) · BMC Medicine · doi:10.1186/1741-7015-7-40 · Cited by 60 · see citing works
Phenotyping the heterogeneity of chronic obstructive pulmonary disease
Barker, B. L., & Brightling, C. E. (2012) · Clinical Science · doi:10.1042/cs20120340 · Cited by 56 · see citing works
Steurer, J., Held, U., Spaar, A., Bausch, B., Zoller, M., Hunziker, R., & Bachmann, L. M. (2011) · BMC Medicine · doi:10.1186/1741-7015-9-56 · Cited by 52 · see citing works
Self-citationMills, E. J., Thorlund, K., & Ioannidis, J. P. A. (2012) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2012.07.012 · Cited by 44 · see citing works
Andrade, N. S., Flynn, J. P., & Bartanusz, V. (2013) · The Spine Journal · doi:10.1016/j.spinee.2013.06.071 · Cited by 38 · see citing works
Hui, D. S. C., Ip, M., Ling, T. K. �., Chang, S., Liao, C., Yoo, C., Kim, D. S., YOON, H., Udompanich, V., Mogmeud, S., et al. (2011) · Respirology · doi:10.1111/j.1440-1843.2011.01943.x · Cited by 30 · see citing works
Laue, J., Reierth, E., & Melbye, H. (2015) · npj Primary Care Respiratory Medicine · doi:10.1038/npjpcrm.2015.2 · Cited by 29 · see citing works
García-Sanz, M. T., Pol-Balado, C., Abellás, C., Cánive-Gómez, J.-C., Antón-Sanmartin, D., & González‐Barcala, F. J. (2012) · Multidisciplinary Respiratory Medicine · doi:10.1186/2049-6958-7-6 · Cited by 27 · see citing works
Llor, C., Moragas, A., Miravitlles, M., Mesquita, P., & Córdoba, G. (2022) · Pulmonary Pharmacology & Therapeutics · doi:10.1016/j.pupt.2022.102111 · Cited by 24 · see citing works
Muñoz San José, A., Oreja-Guevara, C., Cebolla Lorenzo, S., Carrillo Notario, L., Rodríguez Vega, B., & Bayón Pérez, C. (2016) · Neurología · doi:10.1016/j.nrl.2015.07.014 · Cited by 14 · see citing works
José, A. M. S., Oreja‐Guevara, C., Lorenzo, S. C., Notario, L. C., Vega, B. R., & Pérez, C. B. (2016) · Neurología (English Edition) · doi:10.1016/j.nrleng.2015.07.003 · Cited by 14 · see citing works
Grossmann, J. A., Aschenbrenner, S., Teichmann, B., & Meyer, P. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1123185 · Cited by 13 · see citing works
Grossmann, J. A., Kölsch, V., Degirmenci, M. G., Aschenbrenner, S., Teichmann, B., & Meyer, P. (2021) · BMC Geriatrics · doi:10.1186/s12877-021-02051-x · Cited by 15 · see citing works
Wang, Z., Alahdab, F., Farah, M. H., Seisa, M. O., Firwana, M., Rajjoub, R., Saadi, S. M., Jawaid, T., Nayfeh, T., & Murad, M. H. (2021) · BMJ Evidence-Based Medicine · doi:10.1136/bmjebm-2021-111667 · Cited by 9 · see citing works
Antibiotics in acute exacerbations of chronic bronchitis
Sethi, S. (2010) · Expert Review of Anti-infective Therapy · doi:10.1586/eri.09.133 · Cited by 8 · see citing works
Sethi, S. (2008) · BMC Medicine · doi:10.1186/1741-7015-6-29 · Cited by 7 · see citing works
Meta-analyses on the Prevention and Treatment of Respiratory Tract Infections
Siempos, I. Ι., Dimοpoulos, G., & Falagas, M. E. (2009) · Infectious Disease Clinics of North America · doi:10.1016/j.idc.2009.01.006 · Cited by 6 · see citing works
Held, U., Steurer-Stey, C. A., Huber, F., Dallafior, S., & Steurer, J. (2012) · BMC Infectious Diseases · doi:10.1186/1471-2334-12-355 · Cited by 6 · see citing works
Self-citationTreatment of acute bacterial exacerbations of chronic bronchitis
Siempos, I. Ι., Michalopoulos, A. S., & Falagas, M. E. (2009) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656560902907734 · Cited by 5 · see citing works
Antibiotics in COPD exacerbations: practice and evidence
Woodhead, M. A. (2009) · Breathe · doi:10.1183/18106838.0504.299 · Cited by 1 · see citing works
Acute exacerbations of COPD: identification of biological clusters and their
Bafadhel, M., McKenna, S., Terry, S., Mistry, V., Reid, C., Haldar, P., McCormick, M. J., Haldar, K., Kebadze, T., Lindblad, K., et al. (2011)
Bhat, S., & Chokroverty, S. (2017) · Springer eBooks · doi:10.1007/978-1-4939-6578-6_42
Miravitlles, M., & Huerta, A. H. (2012) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.717548109.793461826
(2009) · Huisarts en Wetenschap · doi:10.1007/bf03085607
The Role of Respiratory Virus Infection in Adults Hospitalised with Acute Respiratory Illness
Clark, T. W. (2013) · Leicester Research Archive (University of Leicester)
- Authors
- Puhan, M. A., Vollenweider, D., Steurer, J., Bossuyt, P. M., & ter Riet, G.
- Affiliations
- Johns Hopkins University (US)
- University of Zurich (CH)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Puhan, Milo A
- Venue
- BMC Medicine
- Published
- 2008-10-10
- Volume
- 6
- Issue
- 1
- Pages
- 28-28
- ISSN
- 1741-7015 (ISSN-L)
- PMC
- PMC2569060
- OpenAlex
- W2083066812
- Cited by
- 38
- References
- 38
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 4 · 2012: 10
- FWCI
- 0.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (115216)
- Universität Zürich
- Lunge Zürich
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Keywords
- chronic obstructive pulmonary disease, COPD exacerbations, antibiotics, cumulative meta-analysis, treatment failure, antibiotic efficacy
- MeSH terms
- Anti-Bacterial Agents, Humans, Pulmonary Disease, Chronic Obstructive
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