Inhaling antibiotics to treat temporary worsening of lung infection in people with cystic fibrosis

Review question

What evidence is there for using inhaled antibiotics to treat exacerbations (flare ups) of lung infection in people with cystic fibrosis?

Background

Cystic fibrosis is a serious genetic disorder that results in abnormally sticky mucus in several parts of the body. In the lungs this sticky mucus can lead to repeated infections. An exacerbation makes the symptoms of infection more severe. Antibiotics are an essential part of treatment and may be given by mouth (orally), by needle into the blood stream (intravenously) or by inhaling the drug. We wanted to learn if inhaling antibiotics improved general health compared to the other methods. This might mean that people with cystic fibrosis could avoid hospitalisation for intravenous antibiotics and some side effects of intravenous treatment. Inhaling the antibiotics would also be easier for people who have difficulty with access to their veins. This is an updated version of the review.

Search date

We last looked for evidence on 7 March 2022.

Study characteristics

We found five trials comparing different ways of giving antibiotics when treating exacerbations in a total of 183 people with cystic fibrosis. Two trials compared inhaled antibiotics alone to intravenous antibiotics alone (77 participants) and three trials compared a combination of inhaled and intravenous antibiotics to intravenous antibiotics alone (106 participants). In all trials, the inhaled antibiotics were compared to the same antibiotics given intravenously. The numbers of participants in each trial ranged from 16 to 62.

Key results

Inhaled antibiotics alone versus intravenous antibiotics alone

One trial (18 participants) reported a perceived improvement in lifestyle in both groups, but neither trial reported on time off work or school. Both trials measured lung function, but neither reported any difference between treatment groups. One trial (18 participants) reported no difference in the need for additional antibiotics and the second trial (59 participants) reported on the length of time until the next exacerbation - there was no difference between inhaled or intravenous antibiotics for either outcome. Only one trial (18 participants) measured adverse events and sputum microbiology, but did not find any difference between treatments for either outcome.

Inhaled antibiotics plus intravenous antibiotics versus intravenous antibiotics alone

One trial found that there is likely no difference in quality of life between treatments. All of the trials reported lung function, but found no difference between groups. One trial showed there to be little or no difference in the time until the next exacerbation. None of the trials reported on the need for additional antibiotics; however, one trial (28 participants) found no difference in the number of hospital admissions between groups. There may be no difference between groups in adverse events and one trial (62 participants) reported no difference in the appearance of antibiotic-resistant organisms.

Certainty of the evidence

We graded the certainty of the evidence as very low or low. We had concerns since only one trial stated how the participants were diagnosed with CF or how they defined an exacerbation. It was not possible to keep secret which treatment the participants were receiving, as the trials compared different ways of giving the antibiotics; we thought this would likely influence some of the results. We were not sure whether the participants were put into the different groups truly at random and we do not know how this might have affected the results.

Authors' conclusions: 

We identified only low- or very low-certainty evidence to judge the effectiveness of inhaled antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis. The included trials were not sufficiently powered to achieve their goals. Hence, we are unable to demonstrate whether one treatment was superior to the other or not. Further research is needed to establish whether inhaled tobramycin may be used as an alternative to intravenous tobramycin for some pulmonary exacerbations.

Read the full abstract...
Background: 

Cystic fibrosis is a genetic disorder in which abnormal mucus in the lungs is associated with susceptibility to persistent infection. Pulmonary exacerbations are when symptoms of infection become more severe. Antibiotics are an essential part of treatment for exacerbations and inhaled antibiotics may be used alone or in conjunction with oral antibiotics for milder exacerbations or with intravenous antibiotics for more severe infections. Inhaled antibiotics do not cause the same adverse effects as intravenous antibiotics and may prove an alternative in people with poor access to their veins. This is an update of a previously published review.

Objectives: 

To determine if treatment of pulmonary exacerbations with inhaled antibiotics in people with cystic fibrosis improves their quality of life, reduces time off school or work, and improves their long-term lung function.

Search strategy: 

We searched the Cochrane Cystic Fibrosis Group's Cystic Fibrosis Trials Register. Date of the last search: 7 March 2022.

We also searched ClinicalTrials.gov, the Australia and New Zealand Clinical Trials Registry and WHO ICTRP for relevant trials. Date of last search: 3 May 2022.

Selection criteria: 

Randomised controlled trials in people with cystic fibrosis with a pulmonary exacerbation in whom treatment with inhaled antibiotics was compared to placebo, standard treatment or another inhaled antibiotic for between one and four weeks.

Data collection and analysis: 

Two review authors independently selected eligible trials, assessed the risk of bias in each trial and extracted data. They assessed the certainty of the evidence using the GRADE criteria. Authors of the included trials were contacted for more information.

Main results: 

Five trials with 183 participants are included in the review. Two trials (77 participants) compared inhaled antibiotics alone to intravenous antibiotics alone and three trials (106 participants) compared a combination of inhaled and intravenous antibiotics to intravenous antibiotics alone. Trials were heterogenous in design and two were only available in abstract form. Risk of bias was difficult to assess in most trials but, for four out of five trials, we judged there to be a high risk from lack of blinding and an unclear risk with regards to randomisation. Results were not fully reported and only limited data were available for analysis. One trial was a cross-over design and we only included data from the first intervention arm.

Inhaled antibiotics alone versus intravenous antibiotics alone

Only one trial (18 participants) reported a perceived improvement in lifestyle (quality of life) in both groups (very low-certainty evidence). Neither trial reported on time off work or school. Both trials measured lung function, but there was no difference reported between treatment groups (very low-certainty evidence). With regards to our secondary outcomes, one trial (18 participants) reported no difference in the need for additional antibiotics and the second trial (59 participants) reported on the time to next exacerbation. In neither case was a difference between treatments identified (both very low-certainty evidence). The single trial (18 participants) measuring adverse events and sputum microbiology did not observe any in either treatment group for either outcome (very low-certainty  evidence).

Inhaled antibiotics plus intravenous antibiotics versus intravenous antibiotics alone

Inhaled antibiotics plus intravenous antibiotics may make little or no difference to quality of life compared to intravenous antibiotics alone. None of the trials reported time off work or school. All three trials measured lung function, but found no difference between groups in forced expiratory volume in one second (two trials; 44 participants; very low-certainty evidence) or vital capacity (one trial; 62 participants). None of the trials reported on the need for additional antibiotics. Inhaled plus intravenous antibiotics may make little difference to the time to next exacerbation; however, one trial (28 participants) reported on hospital admissions and found no difference between groups. There is likely no difference between groups in adverse events (very low-certainty evidence) and one trial (62 participants) reported no difference in the emergence of antibiotic-resistant organisms (very low-certainty evidence).