Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis.

Cystic fibrosis is a multisystem disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. Intravenous (IV) antibiotics are commonly used in the treatment of acute deteriorations in symptoms (pulmonary exacerbations); however, recently the assumption that exacerbations are due to increases in bacterial burden has been questioned. This is an update of a previously published review. To establish whether IV antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis improve short-term and long-term clinical outcomes. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews and ongoing trials registers. Date of last search of Cochrane Trials Register: 19 June 2024. Randomised controlled trials and the first treatment cycle of cross-over studies comparing IV antibiotics (given alone or in an antibiotic combination) with placebo, or inhaled or oral antibiotics for people with cystic fibrosis experiencing a pulmonary exacerbation. Studies comparing different IV antibiotic regimens were also eligible. We assessed studies for eligibility and risk of bias, and extracted data. Using GRADE, we assessed the certainty of the evidence for the outcomes lung function % predicted (forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)), time to next exacerbation and quality of life. We included 45 studies involving 2810 participants. The included studies were mostly small, and inadequately reported, many of which were quite old. The certainty of the evidence was mostly low. Combined intravenous antibiotics versus placebo Data reported for absolute change in % predicted FEV1 and FVC suggested a possible improvement in favour of IV antibiotics, but the evidence is very uncertain (1 study, 12 participants; very low-certainty evidence). The study did not measure time to next exacerbation or quality of life. Intravenous versus nebulised antibiotics Five studies (122 participants) reported FEV1, with analysable data only from one study (16 participants). We found no difference between groups (moderate-certainty evidence). Three studies (91 participants) reported on FVC, with analysable data from only one study (54 participants). We are very uncertain on the effect of nebulised antibiotics (very low-certainty evidence). In one study, the 16 participants on nebulised plus IV antibiotics had a lower mean number of days to next exacerbation than those on combined IV antibiotics (low-certainty evidence), but we found no difference in quality of life between groups (low-certainty evidence). Intravenous versus oral antibiotics Three studies (172 participants) reported no difference in different measures of lung function. We found no difference in analysable data between IV and oral antibiotic regimens in either FEV1 % predicted or FVC % predicted (1 study, 24 participants; low-certainty evidence) or in the time to the next exacerbation (1 study, 108 participants; very low-certainty evidence). No study measured quality of life. Intravenous antibiotic regimens compared One study (analysed as two data sets) compared the duration of IV antibiotic regimens between two groups (split according to initial antibiotic response). The first part was a non-inferiority study in 214 early treatment responders to establish whether 10 days of IV antibiotic treatment was as effective as 14 days. Second, investigators looked at whether 14 or 21 days of IV antibiotics were more effective in 705 participants who did not respond early to treatment. We found no difference in FEV1 % predicted with any duration of treatment (919 participants; high-certainty evidence) or the time to next exacerbation (information later taken from registry data). Investigators did not report FVC or quality of life. Other comparisons We also found little or no difference in lung function when comparing single IV antibiotic regimens to placebo (2 studies, 70 participants), or in lung function and time to next exacerbation when comparing different single antibiotic regimens (2 studies, 95 participants). There may be a greater improvement in lung function in participants receiving combined IV antibiotics compared to single IV antibiotics (6 studies, 265 participants; low- to very low-certainty evidence), but probably no difference in the time to next exacerbation (1 study, 34 participants; low-certainty evidence). Four studies compared a single IV antibiotic plus placebo to a combined IV antibiotic regimen with high levels of heterogeneity in the results. We are very uncertain if there is any difference between groups in lung function (4 studies, 214 participants) and there may be little or no difference to being re-admitted to hospital for an exacerbation (2 studies, 104 participants). Nine studies (417 participants) compared combined IV antibiotic regimens with a great variation in drugs. We identified no differences in any measure of lung function or the time to next exacerbation between different regimens (low- to very low-certainty evidence). There were mixed results for adverse events across all comparisons; common adverse effects included elevated liver function tests, gastrointestinal events and haematological abnormalities. There were limited data for other secondary outcomes, such as weight, and there was no evidence of treatment effect. The evidence of benefit from administering IV antibiotics for pulmonary exacerbations in cystic fibrosis is often poor, especially in terms of size of studies and risk of bias, particularly in older studies. We are not certain whether there is any difference between specific antibiotic combinations, and neither is there evidence of a difference between the IV route and the inhaled or oral routes. There is limited evidence that shorter antibiotic duration in adults who respond early to treatment is not different to a longer period of treatment. There remain several unanswered questions regarding optimal IV antibiotic treatment regimens.

Hurley MN ，Smith S ，Flume P ，Jahnke N ，Prayle AP ... -  《Cochrane Database of Systematic Reviews》

Macrolide antibiotics (including azithromycin) for cystic fibrosis.

Cystic fibrosis (CF) is a life-limiting genetic condition, affecting over 90,000 people worldwide. CF affects several organs in the body, but airway damage has the most profound impact on quality of life (QoL) and survival. Causes of lower airway infection in people with CF are, most notably, Staphylococcus aureus in the early course of the disease and Pseudomonas aeruginosa at a later stage. Macrolide antibiotics, e.g. azithromycin and clarithromycin, are usually taken orally, have a broad spectrum of action against gram-positive (e.g. S aureus) and some gram-negative bacteria (e.g. Haemophilus influenzae), and may have a modifying role in diseases involving airway infection and inflammation such as CF. They are well-tolerated and relatively inexpensive, but widespread use has resulted in the emergence of resistant bacteria. This is an updated review. To assess the potential effects of macrolide antibiotics on clinical status in terms of benefit and harm in people with CF. If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of macrolide therapy. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals, and abstract books of conference proceedings. We last searched the Group's Cystic Fibrosis Trials Register on 2 November 2022. We last searched the trial registries WHO ICTRP and clinicaltrials.gov on 9 November 2022. We contacted investigators known to work in the field, previous authors and pharmaceutical companies manufacturing macrolide antibiotics for unpublished or follow-up data, where possible. We included randomised controlled trials of macrolide antibiotics in adults and children with CF. We compared them to: placebo; another class of antibiotic; another macrolide antibiotic; or the same macrolide antibiotic at a different dose or type of administration. Two authors independently extracted data and assessed risk of bias. We assessed the certainty of evidence using GRADE. We included 14 studies (1467 participants) lasting 28 days to 36 months. All the studies assessed azithromycin: 11 compared oral azithromycin to placebo (1167 participants); one compared a high dose to a low dose (47 participants); one compared nebulised to oral azithromycin (45 participants); and one looked at weekly versus daily dose (208 participants). Oral azithromycin versus placebo There is a slight improvement in forced expiratory volume (FEV1 % predicted) in one second in the azithromycin group at up to six months compared to placebo (mean difference (MD) 3.97, 95% confidence interval (CI) 1.74 to 6.19; high-certainty evidence), although there is probably no difference at three months, (MD 2.70%, 95% CI -0.12 to 5.52), or 12 months (MD -0.13, 95% CI -4.96 to 4.70). Participants in the azithromycin group are probably at a decreased risk of pulmonary exacerbation with a longer time to exacerbation (hazard ratio (HR) 0.61, 95% CI 0.50 to 0.75; moderate-certainty evidence). Mild side effects were common, but there was no difference between groups (moderate-certainty evidence). There is no difference in hospital admissions at six months (odds ratio (OR) 0.61, 95% CI 0.36 to 1.04; high-certainty evidence), or in new acquisition of P aeruginosa at 12 months (HR 1.00, 95% CI 0.64 to 1.55; moderate-certainty evidence). High-dose versus low-dose azithromycin We are uncertain whether there is any difference in FEV1 % predicted at six months between the two groups (no data available) or in the rate of exacerbations per child per month (MD -0.05 (95% CI -0.20 to 0.10)); very low-certainty evidence for both outcomes. Only children were included in the study and the study did not report on any of our other clinically important outcomes. Nebulised azithromycin versus oral azithromycin We were unable to include any of the data into our analyses and have reported findings directly from the paper; we graded all evidence as being of very low certainty. The authors reported that there was a greater mean change in FEV1 % predicted at one month in the nebulised azithromycin group (P < 0.001). We are uncertain whether there was a change in P aeruginosa count. Weekly azithromycin versus daily azithromycin There is probably a lower mean change in FEV1 % predicted at six months in the weekly group compared to the daily group (MD -0.70, 95% CI -0.95 to -0.45) and probably also a longer period of time until first exacerbation in the weekly group (MD 17.30 days, 95% CI 4.32 days to 30.28 days). Gastrointestinal side effects are probably more common in the weekly group and there is likely no difference in admissions to hospital or QoL. We graded all evidence as moderate certainty. Azithromycin therapy is associated with a small but consistent improvement in respiratory function, a decreased risk of exacerbation and longer time to exacerbation at six months; but evidence for treatment efficacy beyond six months remains limited. Azithromycin appears to have a good safety profile (although a weekly dose was associated with more gastrointestinal side effects, which makes it less acceptable for long-term therapy), with a relatively minimal treatment burden for people with CF, and it is inexpensive. A wider concern may be the emergence of macrolide resistance reported in the most recent study which, combined with the lack of long-term data, means we do not feel that the current evidence is strong enough to support azithromycin therapy for all people with CF. Future research should report over longer time frames using validated tools and consistent reporting, to allow for easier synthesis of data. In particular, future trials should report important adverse events such as hearing impairment or liver disease. More data on the effects of azithromycin given in different ways and reporting on our primary outcomes would benefit decision-making on whether and how to give macrolide antibiotics. Finally, it is important to assess azithromycin therapy for people with CF who are established on the relatively new cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies which correct the underlying molecular defect associated with CF (none of the trials included in the review are relevant to this population).

Southern KW ，Solis-Moya A ，Kurz D ，Smith S ... -  《Cochrane Database of Systematic Reviews》

Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis.

Hurley MN ，Prayle AP ，Flume P 《Cochrane Database of Systematic Reviews》

Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).

Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del is the commonest CF-causing variant (found in up to 90% of people with CF (pwCF)). The F508del variant lacks meaningful CFTR function - faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. Corrective therapy could benefit many pwCF. This review evaluates single correctors (monotherapy) and any combination of correctors (most commonly lumacaftor, tezacaftor, elexacaftor, VX-659, VX-440 or VX-152) and a potentiator (e.g. ivacaftor) (dual and triple therapies). To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del). We searched the Cochrane CF Trials Register (28 November 2022), reference lists of relevant articles and online trials registries (3 December 2022). Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations. Two authors independently extracted data, assessed risk of bias and judged evidence certainty (GRADE); we contacted investigators for additional data. We included 34 RCTs (4781 participants), lasting between 1 day and 48 weeks; an extension of two lumacaftor-ivacaftor studies provided additional 96-week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), 16 dual-therapy RCTs (2627 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and 11 triple-therapy RCTs (1804 participants) (elexacaftor-tezacaftor-ivacaftor/deutivacaftor; VX-659-tezacaftor-ivacaftor/deutivacaftor; VX-440-tezacaftor-ivacaftor; VX-152-tezacaftor-ivacaftor). Participants in 21 RCTs had the genotype F508del/F508del, in seven RCTs they had F508del/minimal function (MF), in one RCT F508del/gating genotypes, in one RCT either F508del/F508del genotypes or F508del/residual function genotypes, in one RCT either F508del/gating or F508del/residual function genotypes, and in three RCTs either F508del/F508del genotypes or F508del/MF genotypes. Risk of bias judgements varied across different comparisons. Results from 16 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non-standard designs (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinically relevant improvements in quality of life (QoL). There was insufficient evidence to determine effects on lung function. No placebo-controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess due to their variety and few participants (all F508del/F508del). Dual therapy In a tezacaftor-ivacaftor group there was one death (deemed unrelated to the study drug). QoL scores (respiratory domain) favoured both lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all time points (moderate-certainty evidence). At six months, relative change in forced expiratory volume in one second (FEV1) % predicted improved with all dual combination therapies compared to placebo (high- to moderate-certainty evidence). More pwCF reported early transient breathlessness with lumacaftor-ivacaftor (odds ratio (OR) 2.05, 99% confidence interval (CI) 1.10 to 3.83; I2 = 0%; 2 studies, 739 participants; high-certainty evidence). Over 120 weeks (initial study period and follow-up), systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice-daily 400 mg lumacaftor-ivacaftor (80 participants). The tezacaftor-ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo (all moderate-certainty evidence): lumacaftor 600 mg (hazard ratio (HR) 0.70, 95% CI 0.57 to 0.87; I2 = 0%; 2 studies, 739 participants); lumacaftor 400 mg (HR 0.61, 95% CI 0.49 to 0.76; I2 = 0%; 2 studies, 740 participants); and tezacaftor (HR 0.64, 95% CI 0.46 to 0.89; 1 study, 506 participants). Triple therapy No study reported any deaths (high-certainty evidence). All other evidence was low- to moderate-certainty. QoL respiratory domain scores probably improved with triple therapy compared to control at six months (six studies). There was probably a greater relative and absolute change in FEV1 % predicted with triple therapy (four studies each across all combinations). The absolute change in FEV1 % predicted was probably greater for F508del/MF participants taking elexacaftor-tezacaftor-ivacaftor compared to placebo (mean difference 14.30, 95% CI 12.76 to 15.84; 1 study, 403 participants; moderate-certainty evidence), with similar results for other drug combinations and genotypes. There was little or no difference in adverse events between triple therapy and control (10 studies). No study reported time to next pulmonary exacerbation, but fewer F508del/F508del participants experienced a pulmonary exacerbation with elexacaftor-tezacaftor-ivacaftor at four weeks (OR 0.17, 99% CI 0.06 to 0.45; 1 study, 175 participants) and 24 weeks (OR 0.29, 95% CI 0.14 to 0.60; 1 study, 405 participants); similar results were seen across other triple therapy and genotype combinations. There is insufficient evidence of clinically important effects from corrector monotherapy in pwCF with F508del/F508del. Additional data in this review reduced the evidence for efficacy of dual therapy; these agents can no longer be considered as standard therapy. Their use may be appropriate in exceptional circumstances (e.g. if triple therapy is not tolerated or due to age). Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar small improvements in QoL and respiratory function with lower pulmonary exacerbation rates. While the effect sizes for QoL and FEV1 still favour treatment, they have reduced compared to our previous findings. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns, but this should be balanced against the blood pressure increase and shortness of breath seen in longer-term adult data when considering lumacaftor-ivacaftor. Data from triple therapy trials demonstrate improvements in several key outcomes, including FEV1 and QoL. There is probably little or no difference in adverse events for triple therapy (elexacaftor-tezacaftor-ivacaftor/deutivacaftor; VX-659-tezacaftor-ivacaftor/deutivacaftor; VX-440-tezacaftor-ivacaftor; VX-152-tezacaftor-ivacaftor) in pwCF with one or two F508del variants aged 12 years or older (moderate-certainty evidence). Further RCTs are required in children under 12 years and those with more severe lung disease.

Heneghan M ，Southern KW ，Murphy J ，Sinha IP ，Nevitt SJ ... -  《Cochrane Database of Systematic Reviews》

Vitamin D for the management of chronic obstructive pulmonary disease.

COPD is a common, preventable and treatable airway disease, and is currently the third leading cause of death worldwide. About one billion people worldwide are estimated to have vitamin D deficiency or insufficiency. Vitamin D deficiency is common among people with COPD, and has been reported to be associated with reduced lung function and increased risk of acute exacerbations of COPD. Several clinical trials of vitamin D to prevent acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and improve COPD control have been conducted, but an up-to-date meta-analysis of all double-blind, randomised, placebo-controlled trials of this intervention is lacking. To assess the effects of vitamin D for the management of acute exacerbations and symptoms for people with COPD. We searched the Cochrane Airways Trials Register and reference lists of articles. We also searched trial registries directly, and contacted the authors of studies in order to identify additional trials. The date of the last search was 24 August 2022. We included double-blind, randomised, placebo-controlled trials of vitamin D or its hydroxylated metabolites, for adults with a clinical diagnosis of chronic obstructive pulmonary disease based on the presence of characteristic symptoms and irreversible airflow obstruction. We did not impose restrictions regarding disease severity or baseline vitamin D status, in order to maximise generalisability. We used standard Cochrane methods. The primary outcome was the rate of moderate or severe exacerbations (requiring systemic corticosteroids, antibiotics or both). We also performed subgroup analyses to determine whether the effect of vitamin D on the rate of moderate or severe exacerbations was modified by baseline vitamin D status, COPD severity or regular inhaled corticosteroid use. The main secondary outcomes of interest were the proportion of participants experiencing one or more exacerbations (moderate or severe), the change in forced expiratory volume in one second (FEV1, % predicted) and the proportion of participants with one or more serious adverse events of any cause, mortality (all-cause) and quality of life. We used GRADE to assess the certainty of evidence for each outcome. We included 10 double-blind, randomised, placebo-controlled trials in this review, involving a total of 1372 adults. Five studies contributed to the primary outcome analysis of the rate of moderate or severe exacerbations requiring systemic corticosteroids, antibiotics or both. The duration of studies ranged from six weeks to 40 months, and all investigated the effects of administering cholecalciferol (vitamin D3). One study included two intervention arms, one where vitamin D3 was given and one where calcitriol (1,25-dihydroxyvitamin D) was given. The majority of participants had mild to moderate COPD, and profound vitamin D deficiency (25-hydroxyvitamin D (25(OH)D) < 25 nmol/L) at baseline was rare (123 participants contributing data to subgroup analysis). Administration of vitamin D or its hydroxylated metabolites results in little to no change in the overall rate of exacerbations requiring systemic corticosteroids, antibiotics or both (rate ratio (RR) 0.98, 95% CI 0.86 to 1.11; 5 studies, 980 participants; high-certainty evidence). Vitamin D supplementation did not influence any meta-analysed secondary outcomes. These were all based on moderate- or high-certainty evidence aside from adverse events and quality of life, which were based on low-certainty evidence. We observed little to no change in the proportion of participants experiencing one or more moderate or severe exacerbations (odds ratio (OR) 0.94, 95% CI 0.72 to 1.24; 5 studies, 980 participants; high-certainty evidence). Additionally, vitamin D probably results in little to no difference in the inter-arm mean change in FEV1 (% predicted) (mean difference 2.82 higher in intervention arm, 95% CI -2.42 to 8.06; 7 studies, 1063 participants; moderate-certainty evidence). There was also probably no effect of vitamin D on the incidence of serious adverse events due to any cause; although we identified an anticipated absolute effect of 36 additional adverse events per 1000 people, the confidence interval included the null hypothesis of no effect (OR 1.19, 95% CI 0.82 to 1.71; 5 studies, 663 participants; moderate-certainty evidence). Vitamin D may have little to no effect on mortality (OR 1.13, 95% CI 0.57 to 2.21; 6 studies, 1019 participants; low-certainty evidence). It also may have little to no effect on quality of life as measured by validated instruments (narrative findings; 5 studies, 663 participants; low-certainty evidence). We assessed one study as being at high risk of bias in at least one domain; this did not contribute data to the meta-analysis of the primary outcome reported above. Sensitivity analysis that excluded this study from the meta-analysed outcome to which it contributed, the inter-arm mean change in FEV1, did not change the findings. We found that administration of vitamin D results in little to no effect on the rate of moderate or severe exacerbations requiring systemic corticosteroids, antibiotics or both or the proportion of participants experiencing one or more exacerbations (moderate or severe) (both high-certainty evidence). Further, vitamin D probably has no effect on the inter-arm difference in change in lung volumes and the proportion of participants with one or more serious adverse event of any cause (both moderate-certainty evidence), and may make little to no difference to mortality or quality of life (both low-certainty evidence). We recommend further research on the balance of benefits and harms of vitamin D supplements in COPD for those with very low or very high starting vitamin D levels, because we assessed the available evidence as low-certainty for these groups.

Williamson A ，Martineau AR ，Jolliffe D ，Sheikh A ，Janssens W ，Sluyter J ，Rafiq R ，de Jongh R ，Griffiths CJ ... -  《Cochrane Database of Systematic Reviews》