Spencer, S, Donovan, Tim, Chalmers, James D, Mathioudakis, Alexander G, McDonnell, Melissa J., Tsang, Anthony, and Leadbetter, Peter
BackgroundBronchiectasis is a common but under-diagnosed chronic disorder characterised by permanent dilation of the airways arising from a cycle of recurrent infection and inflammation. Symptoms including chronic, persistent cough and productive phlegm are a significant burden for people with bronchiectasis, and the main aim of treatment is to reduce exacerbation frequency and improve quality of life.Prophylactic antibiotic therapy aims to break this infection cycle and is recommended by clinical guidelines for adults with three or more exacerbations a year, based on limited evidence. It is important to weigh the evidence for bacterial suppression against the prevention of antibiotic resistance and further evidence is required on the safety and efficacy of different regimens of intermittently administered antibiotic treatments for people with bronchiectasis.ObjectivesTo evaluate the safety and efficacy of intermittent prophylactic antibiotics in the treatment of adults and children with bronchiectasis.Search methodsWe identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted searches on 6 September 2021, with no restriction on language of publication.Selection criteriaWe included randomised controlled trials (RCTs) of at least three months' duration comparing an intermittent regime of prophylactic antibiotics with placebo, usual care or an alternate intermittentregimen. Intermittent prophylactic administration was defined as repeated courses of antibiotics with on-treatment and off-treatment intervals of at least 14 days' duration. We included adults and childrenwith a clinical diagnosis of bronchiectasis confirmed by high resolution computed tomography (HRCT), plain film chest radiograph, or bronchography and a documented history of recurrent chest infections. We excluded studies where participants received high dose antibiotics immediately prior to enrolment or those with a diagnosis of cystic fibrosis, allergic bronchopulmonary aspergillosis(ABPA), primary ciliary dyskinesia, hypogammaglobulinaemia, sarcoidosis, or a primary diagnosis of COPD. Our primary outcomes were exacerbation frequency and serious adverse events. We did not exclude studies on the basis of review outcomes.Data collection and analysisWe analysed dichotomous data as odds ratios (ORs) or relative risk (RRs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures expected by Cochrane. We conducted GRADE assessments for the following primary outcomes: exacerbation frequency; serious adverse events and secondary outcomes: antibiotic resistance; hospital admissions; health-related quality of life.Main resultsWe includedeightRCTs,with interventions ranging from16 to 48weeks, involving 2180 adults. All evaluatedone ofthree types of antibiotics over two to six cycles of 28 days on/o@ treatment: aminoglycosides, ß-lactams or fluoroquinolones. Two studies also included 12 cycles of 14 days on/off treatment with fluoroquinolones. Participants had a mean age of 63.6 years, 65% were women and approximately 85% Caucasian. Baseline FEV1 ranged from 55.5% to 62.6% predicted. None of the studies included children. Generally, there was a low risk of bias in the included studies.Antibiotic versus placebo: cycle of 14 days on/o . Ciprofloxacin reduced the frequency of exacerbations compared to placebo (RR 0.75, 95% CI 0.61 to 0.93; I² = 65%; 2 studies, 469 participants; moderate-certainty evidence), with eight people (95% CI 6 to 28) needed to treat for an additional beneficial outcome. The intervention increased the risk of antibiotic resistance more than twofold (OR 2.14, 95% CI 1.36 to 3.35; I² = 0%; 2 studies, 624 participants; high-certainty evidence). Serious adverse events, lung function (FEV1), health-related quality of life, and adverse ffects did not differ between groups.Antibiotic versus placebo: cycle of 28 days on/o . Antibiotics did not reduce overall exacerbation frequency (RR 0.92, 95% CI 0.82 to 1.02; I²=0%; 8 studies, 1695 participants; high-certainty evidence) butthere were fewer severe exacerbations (OR 0.59, 95% CI 0.37 to 0.93; I²= 54%; 3 studies, 624 participants),though this should be interpretedwith caution due to loweventrates. The risk of antibiotic resistancewas more than twofold higher based on a pooled analysis (OR 2.20, 95% CI 1.42 to 3.42; I² = 0%; 3 studies, 685 participants; high-certainty evidence)and consistent with unpooled data from four further studies. Serious adverse events, time to first exacerbation, duration of exacerbation, respiratory-related hospital admissions, lung function, health-related quality of life and adverse effects did not differ between study groups.Antibiotic versus usual care. We did not find any studies that compared intermittent antibiotic regimens with usual care.Cycle of 14 days on/o versus cycle of 28 days on/o . Exacerbation frequency did not differ between the two treatment regimens (RR 1.02, 95% CI 0.84 to 1.24; I² = 71%; 2 studies, 625 participants; moderate-certainty evidence) However, inconsistencies in the results from the two trials in this comparison indicate that the apparent aggregated similarities may not be reliable. There was no evidence of a difference in antibiotic resistance between groups (OR 1.00, 95% CI 0.68 to 1.48; I² = 60%; 2 studies, 624 participants; moderate-certainty evidence).Serious adverse events, adverse effects, lung function and health-related quality of life did not differ between the two antibiotic regimens.Authors' conclusionsOverall, in adults who have frequent chest infections, long-term antibiotics given at 14-day on/off intervals slightly reduces the frequency of those infections and increases antibiotic resistance. Intermittent antibiotic regimens result in little to no difference in serious adverse events. The impact ofintermittent antibiotic therapy on childrenwithbronchiectasis is unknowndue to an absence of evidence, and further research is needed to establish the potential risks and benefits.