Can microbiologists and infectious diseases physicians contribute to the management of bronchiectasis? A view from Down Under

The second World Bronchiectasis Day was celebrated on July 1, 2023. While many clinicians recognize the importance of bronchiectasis in patients with cystic fibrosis (CF), most cases occur in other patients worldwide, and its burden is underappreciated (1).

Bronchiectasis is a clinical syndrome characterized by chronic cough, sputum production, and recurrent respiratory exacerbations, and the diagnosis is confirmed by computed tomography scans demonstrating abnormally dilated bronchi. As a chronic pulmonary disorder, it ranks third behind asthma and chronic obstructive pulmonary disease and is over-represented in Indigenous populations from high-income countries (2,3). Bronchiectasis is highly heterogenous with multiple different causes. Nevertheless, infection, inflammation, impaired mucociliary clearance, and structural lung injury are interrelated pathobiological features leading to a final common pathway for bronchiectasis, irrespective of the underlying etiology. Each of these four features independently amplifies the other three resulting in a ‘vicious vortex’ (4). Consequently, antibiotics are one of the cornerstones of therapy.

Although the management of patients with bronchiectasis is typically led by pulmonologists, there is an important role for microbiology and infectious disease expertise. The purpose of this editorial is to reflect upon the evidence supporting antibiotic use and antimicrobial stewardship (AMS), and where microbiologists and infectious diseases physicians add value in the context of current treatment guidelines recommending antibiotics for: (i) managing exacerbations, (ii) maintenance therapy to suppress bacterial loads and reduce exacerbations, and (iii) eradicating new pathogens, principally Pseudomonas aeruginosa (5).

The optimal treatment and its duration for pulmonary exacerbations in bronchiectasis are unknown. A single, randomized controlled trial (RCT) in children found oral amoxycillin-clavulanate was superior to placebo at producing clinical resolution and reducing symptom duration after 14 days of treatment (6). No such data exist for adults. While sputum cultures are recommended to guide therapy based on bacterial species, the relevance of antibiotic susceptibility tests (AST) in established infections is questionable (7). Although parenteral antibiotics are given for severe symptoms or if failing oral antibiotic treatment, whether these should be administered as single or combined therapy remains unresolved (8). The current Thoracic Society of Australia and New Zealand (TSANZ) position statement recommends at least 14 days of antibiotic therapy and for this to be combined therapy for P. aeruginosa (5).

Exacerbations in bronchiectasis impair quality-of-life and accelerate pulmonary decline with their prevention a priority for clinicians, patients, and families (9). A meta-analysis of long-term maintenance oral macrolides involving three RCTs (341 subjects) discovered they reduced exacerbation frequency by 51% and were associated with improved quality-of-life, but not lung function (10). Another meta-analysis for inhaled antibiotics in 16 RCTs (2,597 subjects) found that while bacterial load was reduced >100-fold, exacerbation frequency was only reduced 19%, and without improving quality-of-life or lung function (11). Heterogeneity of trial design and participants complicates interpreting these data and has contributed to inconsistent outcomes for inhaled antibiotic trials. Both macrolide and inhaled antibiotics were also associated with emergence of antibiotic resistance (10,11). The TSANZ position statement recommends long-term oral macrolides for those possessing the ‘frequent exacerbator phenotype’ (≥3 exacerbations requiring antibiotics in the previous 12 months) and reserves inhaled antibiotics for when macrolides are contraindicated, poorly tolerated, or have failed to reduce exacerbation frequency (5).

P. aeruginosa is a risk factor for exacerbations and disease progression (1,5). Data supporting eradication therapy in bronchiectasis are limited to before-and-after studies, a single RCT where all received intravenous anti-pseudomonal therapy for 2 weeks followed by inhaled tobramycin or placebo for 3 months, and RCTs of inhaled antibiotics with eradication as a secondary outcome (5). The sole RCT and before-and-after studies reported improved quality-of-life and reduced exacerbations and hospitalizations following P. aeruginosa eradication (5), while the inhaled antibiotic meta-analysis resulted in >3-fold increased sputum bacterial eradication, but without a consistent link between eradication and clinical benefit (10). The TSANZ position statement recommends eradication therapy for newly detected P. aeruginosa lowers airway infections but not for other respiratory pathogens, and in the absence of robust evidence, it provides several treatment options (5).

The importance of AMS as a means of facilitating the best outcomes while reducing toxicity, antibiotic resistance, and costs is recognized in CF, but it has gained less traction in bronchiectasis (12). Nonetheless, challenges for AMS are likely to be similar for both conditions. These include: educating clinicians about AMS and overcoming reluctance to modify familiar antibiotic regimens; collecting adequate respiratory specimens from non-expectorating patients for surveillance purposes and treating exacerbations; interpreting polymicrobial culture results; failure of AST (compared with knowing the bacterial species) to predict clinical responses to antibiotic treatment of chronic lung infections; uncertainty over the clinical significance of emerging antibiotic resistance in pathogens associated with bronchiectasis, and the limited evidence base in bronchiectasis to guide antibiotic therapy (4,5,12,13).

Large knowledge gaps exist in understanding bronchiectasis. The Box illustrates where microbiologists and infectious diseases physicians can help implement AMS as well as seeking answers to mechanistic and clinical questions and contribute to the design and determining microbiologic endpoints of RCTs in bronchiectasis. The heterogenous nature of bronchiectasis is a major clinical challenge requiring patients to be categorized by their phenotype (observable characteristics linked to outcomes; eg, frequent exacerbations and P. aeruginosa) and endotype (biological mechanisms linked to clinical outcomes or treatment responses; eg, total bacterial load and microbiome) to allow treatable traits (therapeutic targets identified by pheno-endotyping) to be managed by precision (personalized) medicine. Further research is needed to identify robust pheno-endotypes and validated biomarkers. Just like AMS where the right antibiotic regimen is prescribed for the right patient, it is important to ensure in RCTs the right patients are assigned the right antibiotic and the right endpoints are measured. So, yes microbiologists and infectious diseases physicians can play an important role as demonstrated over several decades by the Calgary CF and Bronchiectasis clinics (14,15).

Box:

Where microbiologists and infectious diseases physicians can help implement AMS and contribute to research in understanding and managing bronchiectasis

AMS
Aims	Enhance patient outcomes, reduce antibiotic resistance, decrease costs
Goals	Foster relationships with bronchiectasis clinical teams
	Educate clinical teams on the benefits of AMS
	Advise on antibiotic regimens for exacerbations, maintenance, and eradication
	Provide advice on treating difficult infections, such as NTM-PD and multi-drug resistant organisms
	Supply local AST results to guide empiric therapy for exacerbations/eradication
	Educate, advise, and help implement infection control in multiple settings
Research
AMS	How this impacts upon clinical outcomes, antibiotic resistance, and costs
Translational	Develop experimental models to understand the pathobiology of bronchiectasis
	Map respiratory metagenomics and metatranscriptomics at all stages of the disease
	If respiratory viruses influence the development and dynamics of lung microbiota
	Characterize endotypes by multi-omics to identify biomarkers and therapeutic targets
	Identify and validate non-invasive biomarkers of lower airway infections
	Develop, cheap, reliable, point-of-care microbiologic tests
	Determine the AST which best predicts the clinical response to antibiotic treatments in patients with chronic biofilm-mediated lung infections
	Explore the genetic and phenotypic mechanisms of antibiotic resistance
	Evaluate the role of the resistome, including genotypic–phenotypic correlations
	Developing experimental models mimicking the bronchiectatic lung microenvironment to examine antibiotic mechanisms of action against planktonic and biofilm bacteria
	Characterize the antimicrobial, anti-inflammatory and immunomodulatory effects of antibiotics, such as azithromycin
Clinical	What are the most reliable lower airway specimens in non-expectorating patients?
	What is the clinical significance of detecting multi-resistant non-P. aeruginosa Gram negative bacilli in sputum?
	What role do respiratory viral infections have upon progressive lung disease?
	What is the clinical significance of the lung microbiome and pulmonary dysbiosis?
	Characterize patient phenotypes that have a microbiologic basis
	Determine the most appropriate microbiologic endpoints for RCTs
	Examine feasibility of remote respiratory collections with digital health monitoring
	Identify adaptive platform trials of antimicrobial agents most suited for bronchiectasis studies and how patients can be stratified according to their pheno-endotype
	Managing exacerbations—what antibiotics? single or in combination, dose and duration?
	Maintenance antibiotics—for whom and when, and what dosing regimen, and duration?
	Eradication therapy—which pathogen, what regimen, is it sustained and is it beneficial?
	How to manage difficult to treat infections?—for example, NTM-PD and filamentous fungi
	Is there a place for phage therapy in bronchiectasis?
	Identify the pathogen acquisition pathways in bronchiectasis
	What additional infection and prevention control measures should be routinely administered for bronchiectasis patients in hospital, the clinic and at home?
	Conduct RCTs of novel antimicrobial agents and vaccines in bronchiectasis
	Contribute to cost-effectiveness studies of routine microbiologic testing of respiratory specimens, novel antimicrobial agents and vaccines

AMS = Antimicrobial stewardship; AST = Antibiotic susceptibility tests; NTM-PD = Non-tuberculous mycobacterial pulmonary disease; RCT = Randomized controlled trial.

Funding Statement

KG reports grant funding from the Australian National Health and Medical Research Council (NHMRC) for a Centre of Research Excellence in Bronchiectasis and from the NHMRC and the Australian Medical Research Futures Fund for research projects related to bronchiectasis.

Contributors:

Conceptualization, K Grimwood; Writing - Original Draft, K Grimwood; Writing - Review & Editing, KB Laupland.

Ethics Approval:

N/A

Informed Consent:

N/A

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

N/A

Funding:

KG reports grant funding from the Australian National Health and Medical Research Council (NHMRC) for a Centre of Research Excellence in Bronchiectasis and from the NHMRC and the Australian Medical Research Futures Fund for research projects related to bronchiectasis.

Disclosures:

The authors have no other disclosures.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A