Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis

Background: 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.

Objectives: To establish whether IV antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis improve short-term and long-term clinical outcomes.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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.

Authors' conclusions: 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.