Description of the condition

Bronchiectasis is a chronic airway disease characterised by abnormal destruction and dilation of the large airways, bronchi and bronchioles (Pasteur 2010). It is characterised radiologically by permanent dilation of the bronchi, and clinically by a syndrome of cough, sputum production and recurrent respiratory infections (Chalmers 2014). The pathogenesis of bronchiectasis can be explained by the vicious cycle theory, whereby an initial insult to the airway leads to bronchial wall inflammation and damage, and disordered mucociliary clearance, predisposing the patient to chronic or recurrent infection resulting in further airway damage (Cole 1986; Chalmers 2013). An understanding of this cycle of persistent bacterial colonisation, chronic inflammation of the bronchial mucosa, and progressive tissue destruction is central to the management of bronchiectasis as strategies to arrest both inflammatory and bacterial components are required to limit the progression of lung injury (Cole 1997; Pasteur 2010). Approximately half of presenting cases are idiopathic, but the most common aetiology is a previous chest infection, such as bacterial pneumonia or tuberculosis (Pasteur 2010). Diagnosis is based on identification of one or more abnormally dilated bronchi using high‐resolution computed tomography (HRCT) (Chang 2010; Pasteur 2010). Bacteria most commonly isolated from the airways of patients with bronchiectasis include non‐typeableHaemophilus influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus and Moraxella catarrhalis (Foweraker 2011). Colonising pathogens such as P aeruginosa, H influenzae and M catarrhalis also commonly display antimicrobial resistance arising from intrinsic resistance mechanisms or frequent exposure to antimicrobial agents.

Approximately 29% to 70% of presenting cases are classified as idiopathic. The most commonly assigned aetiology is post‐infectious bronchiectasis, a heterogenous group including patients with childhood respiratory infections like pertussis, bacterial pneumonia or tuberculosis (Pasteur 2010). Diagnosis is based on identification of one or more abnormally dilated bronchi using HRCT (Chang 2010; Pasteur 2010). The main aim of therapeutic management is reduction of symptoms, such as cough, breathlessness and expectoration, reduction of the number and duration of exacerbations and improvement in quality of life (Chalmers 2015; Pasteur 2010).

Bronchiectasis was once considered a relatively rare disease but recent studies have suggested an increasing prevalence, particularly in those aged over 75 years (Weycker 2005), and higher prevalence rates in low‐income and middle‐income countries (Habesoglu 2011). Globally, it is estimated that prevalence in adults will increase from about 2.4 million in 2012 to over 3 million by 2020 (Polverino 2014). In the UK, point prevalence rates per 100,000 rose from 350.5 to 566.1 in women and from 301.2 to 485.5 in men over a nine‐year period, reflecting an increase of more than 60% and approximately 263,000 adults living with bronchiectasis in 2013 (Quint 2016). Similarly, incidence rates per 100,000 person‐years over the same period rose from 21.2 to 35.2 in women and from 18.2 to 26.9 in men, a 63% increase, with over 15,000 new cases in 2013. The prevalence per 10,000 across Europe ranges from 6.6 in Germany to 7.9 in Sweden and 36.2 in Spain (Miravitlles 2016; Ringshausen 2015).

The disease has a significant impact on children with worse quality of life in younger children and those with more frequent exacerbations (Kapur 2012). Bronchiectasis is also more common in some indigenous groups where prevalence may be as high as 16 per 1000 among southwest Alaskan children and 15 per 1000 in Australian Aboriginal and Torres Strait Islander children (Chang 2002). Furthermore, one study reported an incidence of 3.7 per 100,000 per year among New Zealand children aged under 15 years. This equates to an overall prevalence of 1 per 3000 children and 1 per 625 Pacific children (Twiss 2005). It also demonstrates that the incidence rate among children in New Zealand is almost seven times higher than those from Finland (Twiss 2005).

An improvement in diagnosis resulting from easier access to high quality CT scanners, and increased awareness of symptoms common to bronchiectasis and other lung diseases, have been cited as factors contributing to increased prevalence (Goeminne 2016).

Non‐cystic fibrosis (CF) bronchiectasis places an increasing burden on healthcare systems internationally (Redondo 2016; Chalmers 2015), with patients experiencing a high rate of exacerbations, hospital admissions and attributable mortality (Chalmers 2015). Patients colonised with P aeruginosa and those with a more frequent annual exacerbation rate have an accelerated decline in lung function, reduced health‐related quality of life (measured using the St George's Respiratory Questionnaire, SGRQ), increased risk of hospitalisation and increased mortality risk (Evans 1996; Martinez‐Garcia 2007; Wilson 1997). A history of exacerbations, and particularly severe exacerbations, low body mass index, chronic bacterial infection, low forced expiratory volume in one second (FEV₁)percentage predicted, a higher proportion of affected lobes and more breathlessness are also associated with an increased risk of hospitalisation and mortality (Chalmers 2014; Rogers 2014; Seitz 2010). Average European mortality rates per 100,000 general population are estimated at 0.3 in 27 of the 28 European Union (EU) countries (ranging from 0.01 in Germany to 1.18 in the UK) and 0.2 in nine non‐EU countries (ranging from 0.01 in Azerbaijan to 0.67 in Kyrgyzstan), based on 2005 to 2009 data (Gibson 2013). More recent UK figures estimate age‐adjusted mortality rates to be more than twice (2.26 in women, 2.14 in men) that of the general population (Quint 2016).

Bronchiectasis care is associated with substantial resource use. A recent Spanish study reported a mean direct annual medical cost for adult patients with bronchiectasis of EUR 4671, escalating with disease severity (de la Rosa 2016). Furthermore, factors such as FEV₁ percentage predicted, age, Pseudomonas colonisation and hospitalisation may independently influence health care costs. A USA‐based study reported an annual increase of USD 2319 in overall costs and USD 1607 in respiratory‐related costs in patients with bronchiectasis compared with matched case‐controls, attributed primarily to an increase of two outpatient visits and 1.6 respiratory‐related visits per patient per year (Joish 2013).

Description of the intervention

Antibiotics, aiming to treat bacterial infections of the respiratory tract, or to control bacterial colonisation, or both, represent a central component of the treatment of non‐CF bronchiectasis, as they reduce bacterial load, inflammation and consequent tissue destruction in the airways (Chalmers 2012). Long‐term prophylactic antibiotics, administered for more than three months, have proved effective for patients with frequent bronchiectasis exacerbations or those with fewer exacerbations causing significant morbidity, as they appear to decrease the frequency and severity of exacerbations, at the expense of a significant increase in the risk of emerging drug resistance (Hnin 2015). Patients taking continuous antibiotics are more than three times at risk of bacterial resistance compared to those who do not (Hnin 2015). Pathogens isolated in the sputum cultures of these patients during an exacerbation or at stable disease, such as P aeruginosa, H influenzae or M catarrhalis commonly display antimicrobial resistance arising from intrinsic resistance mechanisms or frequent exposure to antimicrobial agents. There is also risk of antibiotic‐related adverse effects, such as hearing impairment and cardiotoxicity (Serisier 2013).

Randomised controlled trials (RCTs) have evaluated different modes of administration, namely oral, intravenous and inhaled, and different classes of antibiotics including but not limited to macrolides, quinolones or polymyxins. Two strategies for the administration of long‐term antibiotics have been described: (I) continuous and (ii) intermittent administration. In contrast to continuous, intermittent refers to the repeated prophylactic administration of courses of antibiotics with predefined duration and intervals. Examples include one short course of antibiotics every month; month on and month off; or during the winter months. This review will include intermittent antibiotic therapy where administration is at predefined regular intervals over a duration of at least three weeks, and where patients are not receiving concomitant prophylactic antibiotics. We will compare continuous versus intermittent administration of long‐term prophylactic antibiotics for at least three months.

How the intervention might work

There is a strong relationship between airway bacterial infection and disease morbidity in bronchiectasis for example, patients chronically infected with P aeruginosa have a three‐fold increase in mortality, a 6.5 times increase in hospital admission rate and an average of one additional exacerbation per patient per year, when compared to patients not chronically infected with P aeruginosa (Finch 2015). Other commonly isolated bacteria such as H influenzae and M catarrhalis also drive an increase in neutrophilic inflammation (Chalmers 2012) and are associated with an increased risk of severe exacerbations (Chalmers 2014). Antibiotic treatment aims to suppress neutrophilic inflammation, reduce bacterial load and thereby improve clinical outcomes (Brodt 2014). Continuous administration of antibiotic treatment is based on the assumption that chronic infection cannot be eradicated, and must therefore be continuously suppressed to prevent a return of bacterial load, increased inflammation and a recurrence of symptoms (Haworth 2014).

The principal of intermittent treatment is that with continuous exposure to antibiotics, bacteria become resistant and treatment may lose its effectiveness (Chalmers 2015). On the contrary, intermittent administration of antibiotics might remove or limit the antibiotic selection pressure and, consequently, prevent the development of resistance. While data are lacking on the impact of intermittent versus continuous administration of antibiotics on the development of antibiotic resistance among patients with bronchiectasis, there is ample indirect evidence. Characteristically, in a large retrospective analysis of mechanically‐ventilated patients with nosocomial infections, it was demonstrated that an interval of at least 20 days between serial courses of antibiotics is associated with a 24% reduction in development of resistance (Hui 2013).

An additional advantage of intermittent antibiotic administration is a reduced treatment burden to patients and that continuous administration may result in more side effects as a result of higher cumulative exposure of the patient to antibiotics.

Why it is important to do this review

While long‐term antibiotic treatments given both orally and via inhalation are part of the standard care for patients with bronchiectasis (Chalmers 2015), there is no agreement on the optimal method of delivery of antibiotic therapies. It is common practice to administer both oral and inhaled antibiotics daily (Altenburg 2013; Haworth 2014), on alternate days (Wong 2012), month on and month off (Barker 2014) or during the winter months where patients may experience more exacerbations. International guidelines are unable to comment on which method of antibiotic administration is most effective or is associated with the lowest rates of adverse events or antibiotic resistance. A European Respiratory Society/European Bronchiectasis Network (EMBARC) task force produced 22 consensus recommendations for future research into bronchiectasis, including "Studies should evaluate whether cyclic or continuous administration of long‐term antibiotics is superior both in terms of clinical efficacy and the emergence of resistance" (Aliberti 2016). As this was determined to be an important clinical question by both patients and physicians, this systematic review aims to evaluate the current evidence for continuous vs intermittent administration of antibiotic treatment in bronchiectasis.