Revisiting the Use of Antibiotics to Prevent COPD Exacerbation: Is Doxycycline the Answer?

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory respiratory disease and a leading contributor to global disease burden as one of the top three causes of death worldwide (1). In 2019, COPD led to 3.28 million deaths and 74.43 million disability-adjusted life-years (2). Exacerbations complicate the clinical course of COPD and have been related to poor quality of life, decline in lung function, and increased mortality (3). It is estimated that 30–50% patients with COPD experience at least one exacerbation every year. Prevention of COPD exacerbation is a major goal of COPD management, with multiple modalities of interventions available (1). The prophylactic use of antibiotics in select patients with COPD has been suggested as one strategy to prevent COPD exacerbation. In a recent Cochrane review, prophylactic antibiotic use in patients with stable COPD decreased the odds of exacerbation by 43% (odds ratio, 0.57; 95% confidence interval, 0.42–0.78), with the number needed to treat to prevent one person with exacerbation being eight (4). This benefit was demonstrated across studies examining continuous or intermittent antibiotic regimens. A subsequent Cochrane review compared the use of different classes of prophylactic antibiotics in patients with COPD and found that macrolides were the only class of drugs whose use increased the time to a subsequent exacerbation and was associated with improved quality of life (5). Use of quinolones and tetracyclines was not associated with any clear benefit. The Global Initiative for Chronic Obstructive Lung Disease strategy recommends considering the addition of macrolides, specifically azithromycin, in non–current smokers with COPD who continue to experience exacerbations despite treatment with a combination therapy of a long-acting β-agonist, a long-acting muscarinic agent, and an inhaled corticosteroid or in those with a baseline blood eosinophil count <100 cells/μl (1). It is noteworthy that data demonstrating the efficacy and safety of azithromycin use to prevent COPD exacerbations beyond 1 year are lacking.

In this issue of the Journal, Allinson and colleagues (pp. 549–558) present their findings from a study of 222 patients with moderate to very severe COPD and a history of exacerbation who were randomized to receive 100 mg doxycycline or placebo over a 12-month period (6). The COPD exacerbation rate was the primary outcome of interest. Other outcomes of interest included time to the first COPD exacerbation, annual rate of exacerbations, COPD-related hospital admissions, change in lung functions, respiratory health status, and C-reactive protein levels. Although there were no differences between the two groups in treated exacerbations requiring hospitalization, the investigators demonstrated, in a prespecified subgroup analysis, that doxycycline reduced exacerbations in patients with severe COPD and eosinophil counts <300 cells/μl. Furthermore, there was no difference in FEV₁ between the two study groups, whereas health status was worse in the doxycycline group. Although the numbers of adverse events were generally similar, a higher incidence of gastrointestinal adverse effects was noted with the use of doxycycline. The authors must be commended for conducting a long-term study to answer an important question without industry sponsorship, but certain aspects of the study design merit a discussion. The investigators used a clinical symptom diary or, when not available, healthcare use to determine COPD exacerbation in their study. This is quite different from other recent trials investigating prophylactic antibiotic use in COPD in which exacerbations were determined based on the need for treatment with systemic steroids, antibiotics, or both (7, 8). Another surprising finding of the study was the fact that doxycycline reduced exacerbations in patients with severe disease but not in those with very severe disease. This might be counterintuitive considering that the severity of COPD at baseline predicts a higher risk of severe exacerbation and subsequent morbidity and mortality (9). However, in the investigators’ defense, the study was not adequately powered to study the outcomes in the subgroup of participants with very severe COPD (n = 18), and a better strategy would have been to group all the patients with severe disease (i.e., FEV₁ <50%) and compare them with those with moderate disease (FEV₁ of 50% to <80%) for outcome analysis.

Evidence suggests that exacerbations of COPD are heterogenous, with several proposed phenotypes and endotypes, including bacterial exacerbations, viral exacerbations, eosinophilic exacerbation, and pauciinflammatory exacerbations. To further understand the potential mechanism of action of doxycycline in patients with stable COPD, one must understand the role of bacterial infections on the pathogenesis of COPD and its exacerbations. Doxycycline is a tetracycline antibiotic that works by inhibiting bacterial growth, with a half-life of 12–25 hours (10). In addition to contributing to airway inflammation, bacteria play a key role in the disease process, with data showing that patients with increased proteobacteria and lower microbiome diversity tend to have more severe disease, more frequent exacerbations, lower FEV₁, and lower blood eosinophil counts (11). This may account for the beneficial effect of doxycycline seen in this study in the subgroup of patients with severe disease with low blood eosinophil counts. Apart from the antibiotic properties, several biological properties of doxycycline have been proposed, mostly based on studies in animal models. These include inhibition of bacterial products from stimulating inflammation, blockade of leukocyte migration by chelating intracellular calcium, inhibition of phospholipase A2 and subsequent formation of inflammatory mediators, and suppression of proinflammatory cytokine and nitric oxide synthesis (12). However, in humans, these suggested mechanisms were not demonstrated in a 3-week clinical study in patients with stable COPD (N = 41), as doxycycline failed to demonstrate an effect on IL-6, IL-8, neutrophil-derived myeloperoxidase, or matrix metalloproteinases levels (13). It is also worth mentioning that previous randomized controlled trials failed to show a benefit of doxycycline prophylaxis in COPD (14, 15) (Table 1).

Table 1.

Randomized Controlled Trials of Prophylactic Doxycycline in Stable Chronic Obstructive Pulmonary Disease

Study	COPD Characteristics	Treatment Arms	Treatment Duration	Outcomes
Brill et al., 2015 (14)	•Aged ⩾45 yr •FEV1 <80% predicted and chronic productive cough	•Doxycycline 100 mg/d •Azithromycin 250 mg 3× per week •Moxifloxacin 400 mg, 5× every 4 wk •Placebo	13 wk	•No difference in bacterial load
Shafuddin et al., 2015 (15)	•Aged ⩾45 yr •⩾20 pack-years smoking •⩾3 confirmed moderate/severe COPD exacerbations in past 2 yr	•Doxycycline 100 mg/d + roxithromycin 300 mg/d •Roxithromycin 300 mg/d •Matching placebos	12 wk	•No difference in annualized exacerbation rates •No difference in spirometry or quality of life •More nausea in active treatment arms
Allinson et al., 2023 (6)	•Aged ⩾45 yr •FEV1 <80% predicted •⩾10 pack-years smoking •⩾1 exacerbation in past 12 mo	•Doxycycline 100 mg/d •Matching placebo	12 mo	•No difference in exacerbations •Subgroup analysis •Benefit noted with doxycycline in patients with severe disease and blood eosinophils <300/μl •More gastrointestinal adverse effects in doxycycline arm

Definition of abbreviations: COPD = chronic obstructive pulmonary disease.

In summary, even though this study failed to demonstrate with strong evidence the long-term efficacy of doxycycline in the prevention of COPD exacerbations in the general COPD population, its results shed light on the fact that this strategy may be beneficial in a subgroup of patients with severe disease with low blood eosinophil counts. Future studies need to further investigate and validate these findings in this subgroup of patients.