Use of long-term inhaled antibiotics and macrolides: insights from the four global bronchiectasis registries

Two of the most widely used antibiotic treatments—some also conferring anti-inflammatory effects—for managing chronic bronchial infection in patients with bronchiectasis are long-term inhaled antibiotics (IAs) (1) and long-term macrolides, particularly azithromycin (2). Despite numerous attempts, no IA has yet received formal approval from regulatory agencies such as the Food and Drug Administration (FDA) or European Medicines Agency (EMA) for their use in bronchiectasis. Nevertheless, several meta-analyses have demonstrated their efficacy in bronchiectasis patients with chronic bronchial infection due to Pseudomonas aeruginosa (PA)—probably the most clinically and functionally devastating condition in bronchiectasis (3,4). These treatments are particularly effective in reducing both the frequency and severity of exacerbations, with minimal systemic adverse effects (1,2).

Macrolides, on the other hand, are administered long-term and at lower-than-standard doses, primarily targeting the chronic bronchial inflammation. Their use extends beyond PA—an organism inherently resistant to this class of antibiotics—to encompass chronic bronchial infections caused by potentially pathogenic bacteria that result in significant symptoms or progressive pulmonary function decline (5). In fact, macrolides currently offer the strongest scientific evidence in bronchiectasis for reducing exacerbations and are supported by three well-designed clinical trials and multiple meta-analyses, all of which consistently demonstrate a global reduction in exacerbation rates (6-9). However, oral administration increases their risk of systemic side effects, some of which necessitate close monitoring. Among these are intestinal dysbiosis and potential complications in individuals with QT interval prolongation, auditory disorders, or non-tuberculous mycobacterial (NTM) isolation—conditions that contraindicate their use as monotherapy. Therefore, prior to initiating macrolide therapy, an electrocardiogram and sputum culture are mandatory, while audiometry is recommended primarily in patients with pre-existing hearing impairment (10,11).

Despite the availability of numerous national bronchiectasis guidelines, the European bronchiectasis guidelines are arguably the most widely implemented on a global scale (11). They recommend the use of IAs in cases of the first or a new isolation of PA when systemic antibiotic therapy fails or added to systemic antibiotic, as well as as a first-line therapeutic option for patients with non-PA infections who experience at least three exacerbations per year. For patients with PA infection, long-term macrolides are also indicated to reduce exacerbations when there is either a lack of response to, or intolerance of, long-term IA therapy (10,11).

Nevertheless, both the use of long-term IA or macrolides exhibit marked global geographical variability, as demonstrated by data from the four largest bronchiectasis registries—each substantial in terms of patient numbers and geographic coverage: the European registry [EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration); n=16,963 in 2023] (12), the US registry (n=5,346, in 2023) (13), the Chinese registry (n=9,641 in 2025) (14), and the Indian registry (n=2,195 in 2019) (15). These data, extracted from their most recent publications (with the Indian registry closely aligned with EMBARC), highlight the notable variability in PA isolation rates—a key determinant for the use of these antibiotics.

As shown in Table 1, the use of IA within the EMBARC registry averages 7.7%, ranging from 1.1% in Italy (n=1,657) to 20% in Spain (n=1,000), among countries contributing at least 200 patients. Corresponding PA isolation rates were 33.3% and 36.9%, respectively. Regarding macrolides, EMBARC reports an average usage rate of 17.3%, with the highest in Belgium at 41.3% (n=399) and the lowest in Turkey at 3.6% (n=222), despite a PA isolation rate of 33.3% among 936 patients with respiratory samples. Notably, Italy reported a remarkably low usage rate of both IA (1.1%) and macrolides (6%) in spite of the PA isolation rate of 33%.

Spain also represents a particular case. National data from both historical (2002–2011; n=2,047) and current registries (RIBRON, 2015–present; n=2,631) show IA usage rates of 23.1% and 19.7%, respectively—the figures closely align with the EMBARC data for Spain regarding the current Spanish guidelines. Long-term macrolides use was 21.1% and 19.8%, also consistent with the data from the EMBARC registry (18.4%) (16). Notably, approximately 40% of RIBRON participants are also included in the EMBARC registry.

In the US registry (13), macrolide use is nearly double that of IAs. Long-term macrolide use reaches 41% for those with the presence of NTM compared to 13% without NTM. IA use reaches 9% and 11% in non-NTM and NTM infection, respectively. This is not surprising given that more than half of the US registry participants have NTM present at baseline enrollment into the registry. It should also be noted that participating academic centers in the US registry are specialized centers and have a strong referral bias for patients with NTM lung disease. Given the high percentage of patients with NTM infection in the registry, macrolide monotherapy is carefully avoided to prevent the development of macrolide resistance.

Conversely, in China (14) and India (15), the use of IA is markedly lower than expected. The use of long-term IA and macrolides in China does not exceed 4%, despite a PA prevalence >20%. In India, the use of IA is also very low (3.6%), but not the use of macrolides (12.3%) in accordance with the rate of PA isolation (13.7%).

The considerable global heterogeneity in IA and macrolide use is not easily explained, though several factors may have likely contributed especially the heterogeneity of bronchiectasis in terms of symptoms and exacerbations (17,18) (In China and India, the limited IA availability could partly explains their low rates of use—2.1% and 3.6%, respectively)—whereas macrolides use is slightly higher (approximately 4%) across various regions in China and higher in India accordingly with the PA isolations and the European recommendations. In the US, the high prevalence of NTM infection, and the consequent incorporation of macrolides into standardized therapeutic regimens for NTM, might have driven their increased use. Less clear, however, is the relatively higher IA use in patients with NTM infection, as IA—aside from inhaled amikacin in refractory cases—are not typically indicated.

In Europe, IA and long-term macrolide use is generally independent of the drug availability, with the exception of some Eastern European regions. The most plausible explanation for the broader use of macrolides over IA—particularly in Northern and Western Europe—is the adherence to European guideline recommendations (11). Spain is a notable exception, with a high use of both IA and macrolides (approximately 20%), likely due to the national guidelines advocating for earlier and broader IA use. This recommendation stems from the high prevalence of PA-associated bronchiectasis in Spain (exceeding 25%) and the elevated rates of multidrug-resistant PA, which often necessitate the combined regimens involving multiple IAs and macrolides (12). This strategy may have contributed to a marked decline in PA infection prevalence, from 36.7% in the 2002–2011 Spanish registry to 25.5% currently, though multidrug resistance rates remain high (18).

The global patterns of IA and macrolides use are influenced not only by the drug availability but also by the regional microbiological profiles—particularly PA and NTM prevalence and resistance patterns—as well as adherence to national and international clinical guidelines.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Prof. James D. Chalmers and Prof. Wei-Jie Guan) for the series “Frontiers in Bronchiectasis Management: Translational Science and Practice” published in Journal of Thoracic Disease. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1370/coif). The series “Frontiers in Bronchiectasis Management: Translational Science and Practice” was commissioned by the editorial office without any funding or sponsorship. W.J.G. serves as an unpaid editorial board member of Journal of Thoracic Disease. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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