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Antimicrobial treatment of non-cystic fibrosis bronchiectasis Expert Rev. Anti Infect. Ther. 12(10), 1277–1296 (2014)
Keith Grimwood*1,2, Scott C Bell3,4 and Anne B Chang5–7 1 Griffith Health Institute, Griffith University, Gold Coast, QLD 4222, Australia 2 Department of Infectious Diseases and Immunology and Department of Paediatrics, Gold Coast University Hospital, Gold Coast, QLD 4215, Australia 3 The Queensland Children’s Medical Research Institute, The University of Queensland, Brisbane, QLD 4029, Australia 4 Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD 4032, Australia 5 The Queensland Children’s Medical Research Institute, Queensland University of Technology, QLD 4029, Australia 6 Menzies School of Health Research, Darwin, NT 0820, Australia 7 Department of Respiratory Medicine, Royal Children’s Hospital, Brisbane, QLD 4029, Australia *Author for correspondence: Tel.: +61 7 56787219 Fax: +61 7 56780795 [email protected]
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Bronchiectasis unrelated to cystic fibrosis is characterized by chronic wet or productive cough, recurrent exacerbations and irreversible bronchial dilatation. After antibiotics and vaccines became available and living standards in affluent countries improved, its resulting reduced prevalence meant bronchiectasis was considered an ‘orphan disease’. This perception has changed recently with increasing use of CT scans to diagnose bronchiectasis, including in those with severe chronic obstructive pulmonary disease or ‘difficult to control’ asthma, and adds to its already known importance in non-affluent countries and disadvantaged Indigenous communities. Following years of neglect, there is renewed interest in identifying the pathogenetic mechanisms of bronchiectasis, including the role of infection, and conducting clinical trials. This is providing much needed evidence to guide antimicrobial therapy, which has relied previously upon extrapolating treatments used in cystic fibrosis and chronic obstructive pulmonary disease. While many knowledge gaps and management challenges remain, the future is improving for patients with bronchiectasis. KEYWORDS: amikacin • azithromycin • bronchiectasis • colistin • Haemophilus influenzae • microbiota • non-tuberculous mycobacteria • Pseudomonas aeruginosa • respiratory viruses • tobramycin
Bronchiectasis unrelated to cystic fibrosis (CF) is a chronic pulmonary disorder defined radiographically (usually by high-resolution CT scans) and pathologically as irreversible dilatation of one or more bronchi [1]. While there are multiple causes, the final common pathophysiological pathway for non-CF bronchiectasis is from airway injury and impaired airway clearance following unabated or repeated episodes of infection, inflammation and tissue remodeling. These combine to establish a ‘vicious cycle’ of infection and inflammation, which destroys structural elements within the bronchial wall [2]. Clinically, bronchiectasis is characterized by chronic cough, sputum production and recurrent exacerbations (mostly infective) that can lead to progressive airflow obstruction, respiratory failure and premature death. In young children unable to expectorate, the symptoms are of recurrent or persistent ‘wet’ cough, which often responds poorly to prolonged oral antibiotic courses at initial diagnosis [3]. Once considered an ‘orphan disease’ due to its reduced prevalence in affluent countries,
10.1586/14787210.2014.952282
there is now renewed interest in bronchiectasis. Antibiotics, vaccines and improvement in living standards, nutrition and access to healthcare are attributed to falling bronchiectasis rates in the second half of the last century. However, with increasing use of highresolution CT scans, bronchiectasis is becoming recognized as an important contributor to morbidity and mortality from chronic pulmonary disorders in mainstream affluent countries and not just in non-affluent countries and disadvantaged Indigenous populations living in affluent nations. Not surprisingly, as a neglected and underrecognized condition, there are few published national data on disease burden. In New Zealand, the incidence of bronchiectasis in children aged under 15 years is 3.7 per 100,000 (or 1 in 1700 births, twice the New Zealand rate of CF) [4]. The estimated prevalence is 1 in 3000 and includes 1 in 625 Pacific Island children living in New Zealand. The prevalence in Central Australian and Alaska Indigenous children is much greater at approximately 15–16 per
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1000 (1 in 65 children) [5]. Hospital-based Central Australian Indigenous adult data reported rates exceeding 100 per 100,000 and a cohort study in this population reported more than one-third died over a 5- to 10-year period at a median age of 42.5 years [6]. Although data are sparse, the disease burden in non-affluent countries is likely to be similar or greater [5,7]. Increased prevalence and mortality rates among adults with bronchiectasis in the general population have been reported in many countries, including the USA, Australia and England [8–10]. In a 5% sample of the US Medicare outpatient claims for beneficiaries aged ‡65 years between 2000 and 2007, the prevalence increased by 8.7% per year [8], while annual Australian hospitalization data showing bronchiectasis as the principal diagnosis increased progressively from 14 to 21 per 100,000 population between 1998–99 and 2011–12, respectively [9,11]. Combined mortality data from England and Wales between 2001 and 2007 revealed a 3% annual increase in bronchiectasis-related deaths, such that by 2007 there were almost 1000 deaths attributed to bronchiectasis [10]. Whether these changes represent a true increase in bronchiectasis or increased recognition is uncertain. Indeed, the true disease burden may be greater as studies in adults from primary care and tertiary centers report 29–58% with severe chronic obstructive pulmonary disease (COPD) and up to 40% with difficult to control asthma and a productive cough have radiographic evidence of bronchiectasis [12,13]. While these figures may be biased by patients with more advanced disease, they emphasize the importance of considering bronchiectasis in those with more severe clinical phenotypes, especially if their sputum contains organisms such as Pseudomonas aeruginosa, Aspergillus or non-tuberculous mycobacteria (NTM) species. Bronchiectasis inflicts a substantial burden on the patient and health system with longer hospital admissions, more frequent outpatient visits and greater treatment burden than ageand sex-matched controls with other chronic conditions, such as diabetes and congestive heart failure, at an annual cost in the USA in 2001 of US$630 million [14]. In children with bronchiectasis, the frequency of hospitalized pulmonary exacerbations is the only factor associated independently with deteriorating pulmonary function [15], while in adults increasing age, declining pulmonary function, severe exacerbations, COPD and chronic P. aeruginosa infection predict disease progression and mortality [16–19]. After outlining the various causes of non-CF bronchiectasis and what little is known of its underlying pathogenesis, this review describes the associated microbiology before providing an overview of the aims and principles of antimicrobial therapy and its role in treating bronchiectasis during exacerbations and clinical stability. Etiology & pathogenesis
There are many causes of non-CF bronchiectasis and these vary according to the patient population being studied. The most common etiologies identified, include post-infectious causes, immunodeficiency (especially common variable immunodeficiency), 1278
autoimmune disorders, oropharyngeal aspiration (in those with underlying neuromuscular or swallowing disorders), primary ciliary dyskinesia and allergic bronchopulmonary aspergillosis (ABPA) [20–23]. Identifying an underlying cause is important as this can lead to a change in management [21,22]. In affluent countries, immunodeficiency or immune dysregulation account for the largest proportion of cases in non-Indigenous patients attending specialist clinics [21,23]. In contrast, post-infectious causes (up to 90%) are implicated most commonly in Indigenous children and adults from affluent countries and in children from non-affluent regions [5,6,24]. Nevertheless, no identifiable cause was found in 10–53% of adults and 27–55% of children in studies conducted in affluent settings [20–23,25]. In bronchiectasis, there is a complex interplay between pathogens and impaired host clearance. The pathophysiology is beyond the scope of this article, but the conceptual model is of a ‘vicious cycle’ of chronic infection and dysregulated airway inflammation [2,26], leading to progressive destruction of bronchial walls resulting in dilatation and airflow obstruction once this cycle becomes established. Antibiotics seek to break this cycle by reducing or even eliminating the bacterial load. In pre-bronchiectatic states or in the early stages of bronchial dilatation (prior to irreversible airway destruction), the arrest or breaking of this cycle is particularly important as bronchiectasis may be prevented [27] or even reversed [28]. Microbiology
Respiratory pathogens play a central role in the ‘vicious cycle’ hypothesis of bronchiectasis. They are implicated as inciting agents in susceptible individuals as well as precipitating acute exacerbations. Bacterial virulence factors disrupt ciliary function and damage epithelial cells, while forming bacterial aggregates and biofilms helps these organisms persist in the lungs. The resulting excessive, but ineffective, immune response mediated by neutrophils leads to proteolytic and oxidative tissue damage [29]. Bacterial pathogens are often present in the stable clinical state and their load is directly related to markers of local airway and systemic inflammation, severity of respiratory symptoms, risk of exacerbations and the likelihood of hospitalization [30–32]. Monitoring airway and sputum microbiology helps guide antimicrobial therapy, especially when there is a deterioration or inadequate response to treatment [1]. While the types of organisms found in most studies are similar, their prevalence can vary according to age, region, ethnicity, referral center, underlying cause of bronchiectasis, clinical state (e.g., new or established diagnosis, stable or with an exacerbation), sample site collection (e.g., upper airway, sputum, bronchoalveolar lavage [BAL], protected brush specimens or bronchial washings), recent antibiotic use and the laboratory techniques adopted (e.g., use of selective media or molecular diagnostic techniques, especially for respiratory viruses). Children
Although in older children and adults obtaining induced or spontaneously expectorated sputum is a simple and non-invasive Expert Rev. Anti Infect. Ther. 12(10), (2014)
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Antimicrobial treatment of non-CF bronchiectasis
means of collecting lower airway specimens, this is not possible in children who are too young to expectorate. Unfortunately, upper airway specimens have suboptimal sensitivity and specificity for accurately predicting lower airway pathogens, especially if antibiotics have been used recently, and can only be expected to provide a rough guide to therapy [33,34]. The alternative option is obtaining a BAL, which because of its invasive nature, cost and feasibility for patients living in remote communities is reserved only for those with an initial diagnosis of bronchiectasis or are failing therapy and either unable to provide sputum or have negative sputum cultures [31,35,36]. Non-typeable Haemophilus influenzae (NTHi) is the main bacterial pathogen in respiratory samples (upper airway, sputum or BAL) collected from children with non-CF bronchiectasis, followed by Streptococcus pneumoniae and Moraxella catarrhalis [21,25,36]. Each can be found within biofilms in the lower airways of these young patients [37]. P. aeruginosa is uncommon in young children and, as with Staphylococcus aureus, the possibility of CF should be considered when detected. NTM and Aspergillus species are reported rarely in children [36]. A study using flexible bronchoscopy and BAL was conducted in 113 consecutive Australian children with newlydiagnosed bronchiectasis [25]. All children were in a stable clinical state and using a diagnostic threshold of ‡105 colonyforming units per ml to adjust for potential contamination by upper airway microbiota, H. influenzae was identified in 32%, S. pneumoniae in 14%, M. catarrhalis in 8% and S. aureus in 5% of BAL cultures [25]. Respiratory viruses (principally respiratory syncytial virus and adenovirus) were detected in the BAL fluid of 14 (12%) children and co-detection of respiratory pathogens was found in more than half of those with positive microbiology results. While P. aeruginosa was detected in just seven (6%) children, six had bronchiectasis involving multiple lobes and five had other co-morbidities. A recent study also reported concurrent adenovirus (type C) detections with the common respiratory bacterial pathogens in the BAL of children with bronchiectasis [38]. Adults
NTHi and P. aeruginosa are the predominant bacterial pathogens in adults with non-CF bronchiectasis and are cultured in 26–81 and 9–46% of patients, respectively [6,23,31,32,39]. The wide variation in reported sputum culture prevalence of these two pathogens most likely reflects different patient populations being studied, for example, referral bias from studies conducted in tertiary hospitals or in high-risk Indigenous populations. In a study of 385 patients from Scotland, bacterial pathogens were detected in sputum from 75% of participants [32]. In those with positive cultures, H. influenzae (39%), P. aeruginosa (21%), S. aureus (12%), M. catarrhalis (11%) and S. pneumoniae (10%) were the most common bacteria detected. Patients with P. aeruginosa had more signs of airway inflammation and advanced lung disease than those harboring other organisms [32]. NTM and Aspergillus species can both cause and complicate non-CF bronchiectasis. While earlier reports indicated NTM informahealthcare.com
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was relatively uncommon [31,39,40], there is some evidence NTM infection rates are increasing, involving as many as 5–10% of adult patients. However, whether this is from increased awareness and surveillance for its presence, improved laboratory techniques or confusing transient colonization with persistent infection is uncertain [6,23]. A recent analysis found that less than half of those with positive NTM respiratory cultures fulfilled the criteria for active infection [41]. Bacterial adaptation
Most bacterial pathogens, including NTM, found in bronchiectasis adapt to the nutrient limitations and oxidative stresses within the lung microenvironment by forming aggregates and biofilm communities [42]. Adaptation allows pathogens to persist within mucous plugs and arises from altered gene expression (e.g., phase variability) and changes in the bacterial genome from either spontaneous mutation or horizontal gene transfer. Biofilms in particular have an important role in survival as they can protect the encased organisms from host immune responses and the effects of antibiotics [43]. Biofilms provide a physical and chemical barrier against phagocytosis, host antibodies and antibiotics, while reduced oxygen and nutrient levels within the biofilm slow bacterial growth, further impairing b-lactam, aminoglycoside and fluoroquinolone activity. Moreover, the two most important pathogens in bronchiectasis, NTHi and P. aeruginosa, possess several additional antibiotic resistance mechanisms that operate in both the ‘freeliving’ (planktonic) and sessile (biofilm) states. b-Lactamase production is the dominant resistance mechanism for NTHi strains against b-lactam antibiotics globally, ranging from 10 to 55% of clinical isolates. In recent years, of greater concern has been the emergence of resistant NTHi strains in East Asia and parts of Europe with evidence of altered penicillin-binding proteins and the potential to develop resistance to all commonly prescribed b-lactam antibiotics and worldwide clonal spread [44]. Once it becomes established within the lungs, P. aeruginosa is virtually impossible to eradicate. In addition to forming biofilms, it has several chromosomally encoded ‘intrinsic’ resistance mechanisms, including low outer membrane permeability, constitutive expression of membrane efflux pumps and an inducible chromosomally mediated broad-spectrum b-lactamase, AmpC [45]. Acquired resistance from mutations and horizontal genetic transfer leads to expression of additional membrane efflux pumps, metallo-b-lactamases, altered target sites and cell membrane structures resulting in multi- and pan-resistant strains. Non-classical microorganisms
In addition to the organisms discussed above, there are others associated with bronchiectasis. The more common of these, NTM and Aspergillus, are ubiquitous environmental organisms to which nearly everyone is exposed during their lifetime, and they are discussed briefly below. Both NTM and Aspergillus can be found together in older patients with non-CF 1279
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bronchiectasis [46], possibly because of impaired airway clearance and a common underlying host defense abnormality, such as disruption of the IFN-g pathway, which protects against infection from both organisms [47].
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Non-tuberculous mycobacteria
Of the more than 150 species of NTM, Mycobacterium avium complex, M. kansasii and M. abscessus complex (M. abscessus sensu stricto, M. massiliense and M. bolletii) are the major causes of pulmonary NTM infections [47]. In bronchiectasis, it is often difficult to differentiate between active infection, environmental contamination and transient colonization [48]. Treatment is also challenging, especially for M. abscessus complex infections, because of high levels of (mainly intrinsic) antibiotic resistance, biofilms and the limited effectiveness and toxicity of the few anti-mycobacterial agents available [49,50]. Aspergillus
While Aspergillus can cause up to six different lung diseases, depending upon the underlying host disorder, the one most often associated with bronchiectasis is ABPA [51]. This immunological pulmonary disorder results from hypersensitivity to A. fumigatus. It occurs predominantly in persons genetically predisposed to asthma, and if not recognized and treated, can lead to mucus impaction, central bronchiectasis and fibrosis [52]. ABPA can also be a complication in 2–15% of CF patients where establishing the diagnosis is difficult because of overlapping pulmonary clinical, radiographic and immunological features [51]. Respiratory viruses
Severe viral lower respiratory infections, (e.g., measles and adenoviruses) are associated with bronchiectasis [53]. While respiratory viruses, especially rhinoviruses and influenza, are well-recognized triggers of acute exacerbations in asthma, COPD and CF [54,55], less is known of their role in non-CF bronchiectasis [25,36,56]. Interestingly, in children with CF and non-CF bronchiectasis, rhinovirus loads exceeded 10-fold those with asthma and by 100-fold the levels detected in controls, leading to speculation that chronic bacterial infection and airway inflammation, accompanied by sustained oxidative stress, impair interferon-mediated anti-viral defense pathways [57]. Lower airway microbiota, including anaerobes
Respiratory bacterial pathogens are typically not cultured in 25–50% of sputum or BAL specimens of patients with non-CF bronchiectasis [36]. However, traditional culture methods miss non-cultivable organisms that may be important in assisting disease management. In a study of 40 clinically stable adults, amplification and barcoded pyrosequencing of the 16S ribosomal RNA genes revealed greater bacterial diversity within sputum than detected by culture [58]. Nevertheless, culture still identified high loads of aerobic pathogens in 100% and anaerobes (e.g., Prevotella and Veillonella) in 83% of sputum samples, respectively, while the increased richness found by 1280
sequencing resulted from detecting bacterial populations in low abundance associated with the oral cavity. During exacerbations, the overall bacterial composition did not change with antibiotic treatment, although four of five patients no longer had P. aeruginosa in their sputum [58]. In another study of 41 adults who provided paired sputum and BAL samples, sequencing was found to be more sensitive than culture at detecting H. influenzae (90 vs 29%) and P. aeruginosa (66 vs 27%), respectively [59]. Sputum samples also exhibited a greater diversity of bacteria than BAL, and bacterial community richness correlated with better lung function, while its composition correlated with lung function, sputum neutrophil counts and cough score [59]. A recent study compared microbiota (using bacterial 16S rRNA gene pyrosequencing) among children with CF, protracted bacterial bronchitis or bronchiectasis and the results compared with those obtained from adults with CF or bronchiectasis [60]. All three pediatric disease cohorts shared similar core respiratory microbiota that differed from adult CF and bronchiectasis microbiota. The adult CF and bronchiectasis microbiota also differed from each other, suggesting common early infection airway microbiota diverge within individuals by adulthood. The shared core pediatric microbiota included both traditional pathogens and many species not identified routinely by standard culture [60]. More studies are required to improve our knowledge of the airway microbiome of patients with bronchiectasis. Technical challenges, including standardizing DNA extraction methods, overcoming potential upper airway contamination of lower airway samples and reliably discriminating viable from dead and dying organisms must first be overcome. The contributions of non-bacterial pathogens, (e.g., viruses and fungi) also need to be determined. Importantly, larger longitudinal studies should be conducted to further understand the clinical impact of microbial community profiles, how they correlate with airway inflammatory responses and to identify any additional pathogenic organisms requiring treatment [61]. Antimicrobial management Therapeutic goals
Antibiotics are prescribed in bronchiectasis to reduce symptoms, prevent exacerbations, preserve lung function, improve healthrelated quality of life (QoL) and enhance survival. Importantly, early and effective treatment decreases short and long-term morbidity [15,62]. This also includes treating any underlying disorder, introducing airway clearance techniques, encouraging exercise, optimizing nutrition, avoiding environmental pollutants (including tobacco smoke) and ensuring vaccines are administered according to national recommendations [1,63]. Antibiotics reduce lower airway bacterial load and inflammation. In so doing, the associated risk of exacerbation is reduced and lung function and QoL improves [32,62]. Unfortunately, little high-quality evidence for guiding therapy of bronchiectasis exists. Management is often extrapolated from studies conducted in patients with CF, who are a clinically distinct patient Expert Rev. Anti Infect. Ther. 12(10), (2014)
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Antimicrobial treatment of non-CF bronchiectasis
population [64]. When randomized controlled trials (RCTs) are performed using successful treatments in CF, the results can be disappointing. Increased exacerbations and accelerated pulmonary decline from recombinant deoxyribonuclease (dornase-a) and adverse effects from inhaled tobramycin and aztreonam are examples [65]. These experiences and the realization of the morbidity and mortality from bronchiectasis worldwide have led to a call for better high-level evidence for managing children and adults [66]. Fortunately, after decades of neglect this is now emerging with the recent publication of several multi-center, placebo-controlled RCTs and with other trials underway [65,66]. Antibiotics are prescribed in patients with bronchiectasis to treat acute exacerbations, eradicate P. aeruginosa and strains of methicillin-resistant S. aureus (MRSA) and as long-term agents to suppress bacterial loads and reduce inflammation in those who are chronically infected. Even short courses of antibiotics can improve systemic and local airway inflammatory profiles [32] and increase QoL scores [62], while there is evidence that intensive therapy in children, including aggressive antibiotic management, helps to preserve lung function into adulthood [67–69]. Acute exacerbations
Differentiating between baseline symptoms and an exacerbation can be difficult and while there is no widely adopted ‘gold standard’, symptoms involving at least 72 h of one or more of increased cough, altered sputum character (increased volume, purulence and viscosity), breathlessness, hemoptysis, with or without, constitutional (anorexia, malaise and lethargy) upset are used in adults to diagnose exacerbations, while sputum color can indicate bacterial infection [1,63,70,71]. In nonexpectorating children, exacerbations are identified by an increase in wet cough for at least 72 h [72]. Prompt treatment is important as exacerbations not only impair QoL, but they can result in hospitalization when severe, and if recurrent, there is an increased risk of accelerating pulmonary decline [15,16]. There are no placebo-containing RCTs evaluating the efficacy of antibiotics in exacerbations, although one is enrolling children currently with bronchiectasis from several Australian and New Zealand centers ([73]; ACTRN12612000010897). Child participants experiencing mild-to-moderate exacerbations will receive oral amoxicillin-clavulanate, azithromycin or placebo and their clinical outcomes will be compared on day 14 [73]. Similarly, current evidence is lacking for the choice of antibiotic and treatment duration. Consequently, guidelines make recommendations based upon expert opinion [1,63] and antibiotics are individualized according to antibiotic-related (e.g., safety, efficacy, ease of administration) and patient-related factors (age, co-morbidities, extent of bronchiectasis, severity of the exacerbation) as well as local antibiotic susceptibility profiles, recent antibiotic use and when obtainable prior and current respiratory culture results. Depending upon the severity, and ideally after obtaining sputum for culture, oral antibiotics are usually prescribed for an acute exacerbation. More severe episodes or failure to improve with oral agents require intravenous (iv.) antibiotics informahealthcare.com
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combined with more intensive airway clearance techniques. Although robust evidence is lacking, a course of antibiotics for 14 days is recommended usually [1,63], by which time improvements in cough character, general wellbeing, QoL indicators and inflammatory markers, with reduced sputum volume and purulence, decreased sputum bacterial load or pathogen clearance and a return toward a clinically stable state should be apparent [32,62,74,75]. Higher doses of antibiotics, particularly in under-nourished children with an increased volume of distribution, may be needed to target known or suspected bacterial pathogens within the patient’s lower respiratory tract [63,76,77]. NTHi, S. pneumoniae and M. catarrhalis are the dominant organisms in children [36]. Initial empiric therapy in children with mild-to-moderate exacerbations (e.g., oral amoxicillin-clavulanate) or when exacerbations are severe (e.g., iv. second- or third-generation cephalosporins) should be active against these pathogens. As P. aeruginosa is relatively uncommon in children (usually
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Antimicrobial treatment of non-cystic fibrosis bronchiectasis Expert Rev. Anti Infect. Ther. 12(10), 1277–1296 (2014)
Keith Grimwood*1,2, Scott C Bell3,4 and Anne B Chang5–7 1 Griffith Health Institute, Griffith University, Gold Coast, QLD 4222, Australia 2 Department of Infectious Diseases and Immunology and Department of Paediatrics, Gold Coast University Hospital, Gold Coast, QLD 4215, Australia 3 The Queensland Children’s Medical Research Institute, The University of Queensland, Brisbane, QLD 4029, Australia 4 Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD 4032, Australia 5 The Queensland Children’s Medical Research Institute, Queensland University of Technology, QLD 4029, Australia 6 Menzies School of Health Research, Darwin, NT 0820, Australia 7 Department of Respiratory Medicine, Royal Children’s Hospital, Brisbane, QLD 4029, Australia *Author for correspondence: Tel.: +61 7 56787219 Fax: +61 7 56780795 [email protected]
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Bronchiectasis unrelated to cystic fibrosis is characterized by chronic wet or productive cough, recurrent exacerbations and irreversible bronchial dilatation. After antibiotics and vaccines became available and living standards in affluent countries improved, its resulting reduced prevalence meant bronchiectasis was considered an ‘orphan disease’. This perception has changed recently with increasing use of CT scans to diagnose bronchiectasis, including in those with severe chronic obstructive pulmonary disease or ‘difficult to control’ asthma, and adds to its already known importance in non-affluent countries and disadvantaged Indigenous communities. Following years of neglect, there is renewed interest in identifying the pathogenetic mechanisms of bronchiectasis, including the role of infection, and conducting clinical trials. This is providing much needed evidence to guide antimicrobial therapy, which has relied previously upon extrapolating treatments used in cystic fibrosis and chronic obstructive pulmonary disease. While many knowledge gaps and management challenges remain, the future is improving for patients with bronchiectasis. KEYWORDS: amikacin • azithromycin • bronchiectasis • colistin • Haemophilus influenzae • microbiota • non-tuberculous mycobacteria • Pseudomonas aeruginosa • respiratory viruses • tobramycin
Bronchiectasis unrelated to cystic fibrosis (CF) is a chronic pulmonary disorder defined radiographically (usually by high-resolution CT scans) and pathologically as irreversible dilatation of one or more bronchi [1]. While there are multiple causes, the final common pathophysiological pathway for non-CF bronchiectasis is from airway injury and impaired airway clearance following unabated or repeated episodes of infection, inflammation and tissue remodeling. These combine to establish a ‘vicious cycle’ of infection and inflammation, which destroys structural elements within the bronchial wall [2]. Clinically, bronchiectasis is characterized by chronic cough, sputum production and recurrent exacerbations (mostly infective) that can lead to progressive airflow obstruction, respiratory failure and premature death. In young children unable to expectorate, the symptoms are of recurrent or persistent ‘wet’ cough, which often responds poorly to prolonged oral antibiotic courses at initial diagnosis [3]. Once considered an ‘orphan disease’ due to its reduced prevalence in affluent countries,
10.1586/14787210.2014.952282
there is now renewed interest in bronchiectasis. Antibiotics, vaccines and improvement in living standards, nutrition and access to healthcare are attributed to falling bronchiectasis rates in the second half of the last century. However, with increasing use of highresolution CT scans, bronchiectasis is becoming recognized as an important contributor to morbidity and mortality from chronic pulmonary disorders in mainstream affluent countries and not just in non-affluent countries and disadvantaged Indigenous populations living in affluent nations. Not surprisingly, as a neglected and underrecognized condition, there are few published national data on disease burden. In New Zealand, the incidence of bronchiectasis in children aged under 15 years is 3.7 per 100,000 (or 1 in 1700 births, twice the New Zealand rate of CF) [4]. The estimated prevalence is 1 in 3000 and includes 1 in 625 Pacific Island children living in New Zealand. The prevalence in Central Australian and Alaska Indigenous children is much greater at approximately 15–16 per
2014 Informa UK Ltd
ISSN 1478-7210
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Grimwood, Bell & Chang
1000 (1 in 65 children) [5]. Hospital-based Central Australian Indigenous adult data reported rates exceeding 100 per 100,000 and a cohort study in this population reported more than one-third died over a 5- to 10-year period at a median age of 42.5 years [6]. Although data are sparse, the disease burden in non-affluent countries is likely to be similar or greater [5,7]. Increased prevalence and mortality rates among adults with bronchiectasis in the general population have been reported in many countries, including the USA, Australia and England [8–10]. In a 5% sample of the US Medicare outpatient claims for beneficiaries aged ‡65 years between 2000 and 2007, the prevalence increased by 8.7% per year [8], while annual Australian hospitalization data showing bronchiectasis as the principal diagnosis increased progressively from 14 to 21 per 100,000 population between 1998–99 and 2011–12, respectively [9,11]. Combined mortality data from England and Wales between 2001 and 2007 revealed a 3% annual increase in bronchiectasis-related deaths, such that by 2007 there were almost 1000 deaths attributed to bronchiectasis [10]. Whether these changes represent a true increase in bronchiectasis or increased recognition is uncertain. Indeed, the true disease burden may be greater as studies in adults from primary care and tertiary centers report 29–58% with severe chronic obstructive pulmonary disease (COPD) and up to 40% with difficult to control asthma and a productive cough have radiographic evidence of bronchiectasis [12,13]. While these figures may be biased by patients with more advanced disease, they emphasize the importance of considering bronchiectasis in those with more severe clinical phenotypes, especially if their sputum contains organisms such as Pseudomonas aeruginosa, Aspergillus or non-tuberculous mycobacteria (NTM) species. Bronchiectasis inflicts a substantial burden on the patient and health system with longer hospital admissions, more frequent outpatient visits and greater treatment burden than ageand sex-matched controls with other chronic conditions, such as diabetes and congestive heart failure, at an annual cost in the USA in 2001 of US$630 million [14]. In children with bronchiectasis, the frequency of hospitalized pulmonary exacerbations is the only factor associated independently with deteriorating pulmonary function [15], while in adults increasing age, declining pulmonary function, severe exacerbations, COPD and chronic P. aeruginosa infection predict disease progression and mortality [16–19]. After outlining the various causes of non-CF bronchiectasis and what little is known of its underlying pathogenesis, this review describes the associated microbiology before providing an overview of the aims and principles of antimicrobial therapy and its role in treating bronchiectasis during exacerbations and clinical stability. Etiology & pathogenesis
There are many causes of non-CF bronchiectasis and these vary according to the patient population being studied. The most common etiologies identified, include post-infectious causes, immunodeficiency (especially common variable immunodeficiency), 1278
autoimmune disorders, oropharyngeal aspiration (in those with underlying neuromuscular or swallowing disorders), primary ciliary dyskinesia and allergic bronchopulmonary aspergillosis (ABPA) [20–23]. Identifying an underlying cause is important as this can lead to a change in management [21,22]. In affluent countries, immunodeficiency or immune dysregulation account for the largest proportion of cases in non-Indigenous patients attending specialist clinics [21,23]. In contrast, post-infectious causes (up to 90%) are implicated most commonly in Indigenous children and adults from affluent countries and in children from non-affluent regions [5,6,24]. Nevertheless, no identifiable cause was found in 10–53% of adults and 27–55% of children in studies conducted in affluent settings [20–23,25]. In bronchiectasis, there is a complex interplay between pathogens and impaired host clearance. The pathophysiology is beyond the scope of this article, but the conceptual model is of a ‘vicious cycle’ of chronic infection and dysregulated airway inflammation [2,26], leading to progressive destruction of bronchial walls resulting in dilatation and airflow obstruction once this cycle becomes established. Antibiotics seek to break this cycle by reducing or even eliminating the bacterial load. In pre-bronchiectatic states or in the early stages of bronchial dilatation (prior to irreversible airway destruction), the arrest or breaking of this cycle is particularly important as bronchiectasis may be prevented [27] or even reversed [28]. Microbiology
Respiratory pathogens play a central role in the ‘vicious cycle’ hypothesis of bronchiectasis. They are implicated as inciting agents in susceptible individuals as well as precipitating acute exacerbations. Bacterial virulence factors disrupt ciliary function and damage epithelial cells, while forming bacterial aggregates and biofilms helps these organisms persist in the lungs. The resulting excessive, but ineffective, immune response mediated by neutrophils leads to proteolytic and oxidative tissue damage [29]. Bacterial pathogens are often present in the stable clinical state and their load is directly related to markers of local airway and systemic inflammation, severity of respiratory symptoms, risk of exacerbations and the likelihood of hospitalization [30–32]. Monitoring airway and sputum microbiology helps guide antimicrobial therapy, especially when there is a deterioration or inadequate response to treatment [1]. While the types of organisms found in most studies are similar, their prevalence can vary according to age, region, ethnicity, referral center, underlying cause of bronchiectasis, clinical state (e.g., new or established diagnosis, stable or with an exacerbation), sample site collection (e.g., upper airway, sputum, bronchoalveolar lavage [BAL], protected brush specimens or bronchial washings), recent antibiotic use and the laboratory techniques adopted (e.g., use of selective media or molecular diagnostic techniques, especially for respiratory viruses). Children
Although in older children and adults obtaining induced or spontaneously expectorated sputum is a simple and non-invasive Expert Rev. Anti Infect. Ther. 12(10), (2014)
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Antimicrobial treatment of non-CF bronchiectasis
means of collecting lower airway specimens, this is not possible in children who are too young to expectorate. Unfortunately, upper airway specimens have suboptimal sensitivity and specificity for accurately predicting lower airway pathogens, especially if antibiotics have been used recently, and can only be expected to provide a rough guide to therapy [33,34]. The alternative option is obtaining a BAL, which because of its invasive nature, cost and feasibility for patients living in remote communities is reserved only for those with an initial diagnosis of bronchiectasis or are failing therapy and either unable to provide sputum or have negative sputum cultures [31,35,36]. Non-typeable Haemophilus influenzae (NTHi) is the main bacterial pathogen in respiratory samples (upper airway, sputum or BAL) collected from children with non-CF bronchiectasis, followed by Streptococcus pneumoniae and Moraxella catarrhalis [21,25,36]. Each can be found within biofilms in the lower airways of these young patients [37]. P. aeruginosa is uncommon in young children and, as with Staphylococcus aureus, the possibility of CF should be considered when detected. NTM and Aspergillus species are reported rarely in children [36]. A study using flexible bronchoscopy and BAL was conducted in 113 consecutive Australian children with newlydiagnosed bronchiectasis [25]. All children were in a stable clinical state and using a diagnostic threshold of ‡105 colonyforming units per ml to adjust for potential contamination by upper airway microbiota, H. influenzae was identified in 32%, S. pneumoniae in 14%, M. catarrhalis in 8% and S. aureus in 5% of BAL cultures [25]. Respiratory viruses (principally respiratory syncytial virus and adenovirus) were detected in the BAL fluid of 14 (12%) children and co-detection of respiratory pathogens was found in more than half of those with positive microbiology results. While P. aeruginosa was detected in just seven (6%) children, six had bronchiectasis involving multiple lobes and five had other co-morbidities. A recent study also reported concurrent adenovirus (type C) detections with the common respiratory bacterial pathogens in the BAL of children with bronchiectasis [38]. Adults
NTHi and P. aeruginosa are the predominant bacterial pathogens in adults with non-CF bronchiectasis and are cultured in 26–81 and 9–46% of patients, respectively [6,23,31,32,39]. The wide variation in reported sputum culture prevalence of these two pathogens most likely reflects different patient populations being studied, for example, referral bias from studies conducted in tertiary hospitals or in high-risk Indigenous populations. In a study of 385 patients from Scotland, bacterial pathogens were detected in sputum from 75% of participants [32]. In those with positive cultures, H. influenzae (39%), P. aeruginosa (21%), S. aureus (12%), M. catarrhalis (11%) and S. pneumoniae (10%) were the most common bacteria detected. Patients with P. aeruginosa had more signs of airway inflammation and advanced lung disease than those harboring other organisms [32]. NTM and Aspergillus species can both cause and complicate non-CF bronchiectasis. While earlier reports indicated NTM informahealthcare.com
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was relatively uncommon [31,39,40], there is some evidence NTM infection rates are increasing, involving as many as 5–10% of adult patients. However, whether this is from increased awareness and surveillance for its presence, improved laboratory techniques or confusing transient colonization with persistent infection is uncertain [6,23]. A recent analysis found that less than half of those with positive NTM respiratory cultures fulfilled the criteria for active infection [41]. Bacterial adaptation
Most bacterial pathogens, including NTM, found in bronchiectasis adapt to the nutrient limitations and oxidative stresses within the lung microenvironment by forming aggregates and biofilm communities [42]. Adaptation allows pathogens to persist within mucous plugs and arises from altered gene expression (e.g., phase variability) and changes in the bacterial genome from either spontaneous mutation or horizontal gene transfer. Biofilms in particular have an important role in survival as they can protect the encased organisms from host immune responses and the effects of antibiotics [43]. Biofilms provide a physical and chemical barrier against phagocytosis, host antibodies and antibiotics, while reduced oxygen and nutrient levels within the biofilm slow bacterial growth, further impairing b-lactam, aminoglycoside and fluoroquinolone activity. Moreover, the two most important pathogens in bronchiectasis, NTHi and P. aeruginosa, possess several additional antibiotic resistance mechanisms that operate in both the ‘freeliving’ (planktonic) and sessile (biofilm) states. b-Lactamase production is the dominant resistance mechanism for NTHi strains against b-lactam antibiotics globally, ranging from 10 to 55% of clinical isolates. In recent years, of greater concern has been the emergence of resistant NTHi strains in East Asia and parts of Europe with evidence of altered penicillin-binding proteins and the potential to develop resistance to all commonly prescribed b-lactam antibiotics and worldwide clonal spread [44]. Once it becomes established within the lungs, P. aeruginosa is virtually impossible to eradicate. In addition to forming biofilms, it has several chromosomally encoded ‘intrinsic’ resistance mechanisms, including low outer membrane permeability, constitutive expression of membrane efflux pumps and an inducible chromosomally mediated broad-spectrum b-lactamase, AmpC [45]. Acquired resistance from mutations and horizontal genetic transfer leads to expression of additional membrane efflux pumps, metallo-b-lactamases, altered target sites and cell membrane structures resulting in multi- and pan-resistant strains. Non-classical microorganisms
In addition to the organisms discussed above, there are others associated with bronchiectasis. The more common of these, NTM and Aspergillus, are ubiquitous environmental organisms to which nearly everyone is exposed during their lifetime, and they are discussed briefly below. Both NTM and Aspergillus can be found together in older patients with non-CF 1279
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bronchiectasis [46], possibly because of impaired airway clearance and a common underlying host defense abnormality, such as disruption of the IFN-g pathway, which protects against infection from both organisms [47].
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Non-tuberculous mycobacteria
Of the more than 150 species of NTM, Mycobacterium avium complex, M. kansasii and M. abscessus complex (M. abscessus sensu stricto, M. massiliense and M. bolletii) are the major causes of pulmonary NTM infections [47]. In bronchiectasis, it is often difficult to differentiate between active infection, environmental contamination and transient colonization [48]. Treatment is also challenging, especially for M. abscessus complex infections, because of high levels of (mainly intrinsic) antibiotic resistance, biofilms and the limited effectiveness and toxicity of the few anti-mycobacterial agents available [49,50]. Aspergillus
While Aspergillus can cause up to six different lung diseases, depending upon the underlying host disorder, the one most often associated with bronchiectasis is ABPA [51]. This immunological pulmonary disorder results from hypersensitivity to A. fumigatus. It occurs predominantly in persons genetically predisposed to asthma, and if not recognized and treated, can lead to mucus impaction, central bronchiectasis and fibrosis [52]. ABPA can also be a complication in 2–15% of CF patients where establishing the diagnosis is difficult because of overlapping pulmonary clinical, radiographic and immunological features [51]. Respiratory viruses
Severe viral lower respiratory infections, (e.g., measles and adenoviruses) are associated with bronchiectasis [53]. While respiratory viruses, especially rhinoviruses and influenza, are well-recognized triggers of acute exacerbations in asthma, COPD and CF [54,55], less is known of their role in non-CF bronchiectasis [25,36,56]. Interestingly, in children with CF and non-CF bronchiectasis, rhinovirus loads exceeded 10-fold those with asthma and by 100-fold the levels detected in controls, leading to speculation that chronic bacterial infection and airway inflammation, accompanied by sustained oxidative stress, impair interferon-mediated anti-viral defense pathways [57]. Lower airway microbiota, including anaerobes
Respiratory bacterial pathogens are typically not cultured in 25–50% of sputum or BAL specimens of patients with non-CF bronchiectasis [36]. However, traditional culture methods miss non-cultivable organisms that may be important in assisting disease management. In a study of 40 clinically stable adults, amplification and barcoded pyrosequencing of the 16S ribosomal RNA genes revealed greater bacterial diversity within sputum than detected by culture [58]. Nevertheless, culture still identified high loads of aerobic pathogens in 100% and anaerobes (e.g., Prevotella and Veillonella) in 83% of sputum samples, respectively, while the increased richness found by 1280
sequencing resulted from detecting bacterial populations in low abundance associated with the oral cavity. During exacerbations, the overall bacterial composition did not change with antibiotic treatment, although four of five patients no longer had P. aeruginosa in their sputum [58]. In another study of 41 adults who provided paired sputum and BAL samples, sequencing was found to be more sensitive than culture at detecting H. influenzae (90 vs 29%) and P. aeruginosa (66 vs 27%), respectively [59]. Sputum samples also exhibited a greater diversity of bacteria than BAL, and bacterial community richness correlated with better lung function, while its composition correlated with lung function, sputum neutrophil counts and cough score [59]. A recent study compared microbiota (using bacterial 16S rRNA gene pyrosequencing) among children with CF, protracted bacterial bronchitis or bronchiectasis and the results compared with those obtained from adults with CF or bronchiectasis [60]. All three pediatric disease cohorts shared similar core respiratory microbiota that differed from adult CF and bronchiectasis microbiota. The adult CF and bronchiectasis microbiota also differed from each other, suggesting common early infection airway microbiota diverge within individuals by adulthood. The shared core pediatric microbiota included both traditional pathogens and many species not identified routinely by standard culture [60]. More studies are required to improve our knowledge of the airway microbiome of patients with bronchiectasis. Technical challenges, including standardizing DNA extraction methods, overcoming potential upper airway contamination of lower airway samples and reliably discriminating viable from dead and dying organisms must first be overcome. The contributions of non-bacterial pathogens, (e.g., viruses and fungi) also need to be determined. Importantly, larger longitudinal studies should be conducted to further understand the clinical impact of microbial community profiles, how they correlate with airway inflammatory responses and to identify any additional pathogenic organisms requiring treatment [61]. Antimicrobial management Therapeutic goals
Antibiotics are prescribed in bronchiectasis to reduce symptoms, prevent exacerbations, preserve lung function, improve healthrelated quality of life (QoL) and enhance survival. Importantly, early and effective treatment decreases short and long-term morbidity [15,62]. This also includes treating any underlying disorder, introducing airway clearance techniques, encouraging exercise, optimizing nutrition, avoiding environmental pollutants (including tobacco smoke) and ensuring vaccines are administered according to national recommendations [1,63]. Antibiotics reduce lower airway bacterial load and inflammation. In so doing, the associated risk of exacerbation is reduced and lung function and QoL improves [32,62]. Unfortunately, little high-quality evidence for guiding therapy of bronchiectasis exists. Management is often extrapolated from studies conducted in patients with CF, who are a clinically distinct patient Expert Rev. Anti Infect. Ther. 12(10), (2014)
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Antimicrobial treatment of non-CF bronchiectasis
population [64]. When randomized controlled trials (RCTs) are performed using successful treatments in CF, the results can be disappointing. Increased exacerbations and accelerated pulmonary decline from recombinant deoxyribonuclease (dornase-a) and adverse effects from inhaled tobramycin and aztreonam are examples [65]. These experiences and the realization of the morbidity and mortality from bronchiectasis worldwide have led to a call for better high-level evidence for managing children and adults [66]. Fortunately, after decades of neglect this is now emerging with the recent publication of several multi-center, placebo-controlled RCTs and with other trials underway [65,66]. Antibiotics are prescribed in patients with bronchiectasis to treat acute exacerbations, eradicate P. aeruginosa and strains of methicillin-resistant S. aureus (MRSA) and as long-term agents to suppress bacterial loads and reduce inflammation in those who are chronically infected. Even short courses of antibiotics can improve systemic and local airway inflammatory profiles [32] and increase QoL scores [62], while there is evidence that intensive therapy in children, including aggressive antibiotic management, helps to preserve lung function into adulthood [67–69]. Acute exacerbations
Differentiating between baseline symptoms and an exacerbation can be difficult and while there is no widely adopted ‘gold standard’, symptoms involving at least 72 h of one or more of increased cough, altered sputum character (increased volume, purulence and viscosity), breathlessness, hemoptysis, with or without, constitutional (anorexia, malaise and lethargy) upset are used in adults to diagnose exacerbations, while sputum color can indicate bacterial infection [1,63,70,71]. In nonexpectorating children, exacerbations are identified by an increase in wet cough for at least 72 h [72]. Prompt treatment is important as exacerbations not only impair QoL, but they can result in hospitalization when severe, and if recurrent, there is an increased risk of accelerating pulmonary decline [15,16]. There are no placebo-containing RCTs evaluating the efficacy of antibiotics in exacerbations, although one is enrolling children currently with bronchiectasis from several Australian and New Zealand centers ([73]; ACTRN12612000010897). Child participants experiencing mild-to-moderate exacerbations will receive oral amoxicillin-clavulanate, azithromycin or placebo and their clinical outcomes will be compared on day 14 [73]. Similarly, current evidence is lacking for the choice of antibiotic and treatment duration. Consequently, guidelines make recommendations based upon expert opinion [1,63] and antibiotics are individualized according to antibiotic-related (e.g., safety, efficacy, ease of administration) and patient-related factors (age, co-morbidities, extent of bronchiectasis, severity of the exacerbation) as well as local antibiotic susceptibility profiles, recent antibiotic use and when obtainable prior and current respiratory culture results. Depending upon the severity, and ideally after obtaining sputum for culture, oral antibiotics are usually prescribed for an acute exacerbation. More severe episodes or failure to improve with oral agents require intravenous (iv.) antibiotics informahealthcare.com
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combined with more intensive airway clearance techniques. Although robust evidence is lacking, a course of antibiotics for 14 days is recommended usually [1,63], by which time improvements in cough character, general wellbeing, QoL indicators and inflammatory markers, with reduced sputum volume and purulence, decreased sputum bacterial load or pathogen clearance and a return toward a clinically stable state should be apparent [32,62,74,75]. Higher doses of antibiotics, particularly in under-nourished children with an increased volume of distribution, may be needed to target known or suspected bacterial pathogens within the patient’s lower respiratory tract [63,76,77]. NTHi, S. pneumoniae and M. catarrhalis are the dominant organisms in children [36]. Initial empiric therapy in children with mild-to-moderate exacerbations (e.g., oral amoxicillin-clavulanate) or when exacerbations are severe (e.g., iv. second- or third-generation cephalosporins) should be active against these pathogens. As P. aeruginosa is relatively uncommon in children (usually
