American Journal of Respiratory and Critical Care Medicine

From the Authors:

We thank Martinez-Garcia and colleagues and Wang and colleagues for their thoughtful comments.

By design, we enriched our study sample for those with histories of exacerbations (1), and infection is recognized as a major cause of such exacerbations (2). Therefore, the bacteriostatic action of doxycycline is a probable mechanism of action, as we discuss. Delineating the mechanism responsible is important. Microbial analyses of sputum collected during this clinical trial were not a prespecified trial outcome, so they were not reported as such. Sputum samples were not available from all study participants, but the available samples are the subject of our ongoing research (3).

As with all chronic obstructive pulmonary disease therapies, clinicians must consider the potential risks and benefits of antibiotic prophylaxis when developing personalized chronic obstructive pulmonary disease management plans. The development of antimicrobial resistance is a legitimate concern, and we have shown that this is a frequent occurrence with both doxycycline and azithromycin (4). Although prior clinical trials focused predominantly on macrolides, when such therapy is not an option, some clinicians prescribe prophylactic doxycycline therapy instead (5). This may reflect the substantial impact of exacerbations on their patients (2) and some clinicians’ being familiar with using long-term doxycycline therapy to treat nonrespiratory conditions, such as acne. We hope our study provides useful insights and will drive further work to better understand if doxycycline benefits some of these individuals.

1. Allinson JP, Vlies BH, Brill SE, Law M, Burnside G, Finney LJ, et al. A double-blind, randomized, placebo-controlled trial of long-term doxycycline therapy on exacerbation rate in patients with stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2023;208:549558.
2. Wedzicha JA, Brill SE, Allinson JP, Donaldson GC. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med 2013;11:181.
3. Narayana J, Allinson J, Ivan F, et al. Long-term doxycycline demonstrates microbial perturbation and altered interactomes in COPD: exploratory analysis from a randomized, double-blind, placebo-controlled trial [abstract]. Am J Respir Crit Care Med 2023;207:A2651.
4. Brill SE, Law M, El-Emir E, Allinson JP, James P, Maddox V, et al. Effects of different antibiotic classes on airway bacteria in stable COPD using culture and molecular techniques: a randomised controlled trial. Thorax 2015;70:930938.
5. James GD, Petersen I, Nazareth I, Wedzicha JA, Donaldson GC. Use of long-term antibiotic treatment in COPD patients in the UK: a retrospective cohort study. Prim Care Respir J 2013;22: 271277.
Correspondence and requests for reprints should be addressed to James P. Allinson, COPD Research Group, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Dovehouse Street, London SW3 6LY, UK. Email: .

Originally Published in Press as DOI: 10.1164/rccm.202309-1604LE on September 21, 2023

Author disclosures are available with the text of this letter at


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American Journal of Respiratory and Critical Care Medicine

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