Inhaling antibiotics to treat lung infection in people with cystic fibrosis

Review question

We reviewed the evidence for the benefit of inhaled antibiotics against persistent Pseudomonas aeruginosa infection in people with cystic fibrosis.

Background

Cystic fibrosis is an inherited disease which results in abnormal mucus in several parts of the body. The main part of the body affected is the lungs which are susceptible to infection by certain bacteria. Infection causes inflammation which results in progressive damage to the lungs. As people with cystic fibrosis get older, they are more likely to become infected on a long-term basis with Pseudomonas aeruginosa. This is the most common cause of chronic lung infection in people with CF.

We wanted to find out whether antibiotics targeting Pseudomonas aeruginosa would reduce the effects of infection when they are inhaled into the lungs. We wanted to learn whether this treatment would improve lung function, quality of life and survival. We also looked for any harmful effects.

Search date

The evidence is current to: 13 February 2018.

Trial characteristics

The review included 18 trials with 3042 people with cystic fibrosis aged between five and 56 years of age. The trials lasted from three months to 33 months. Eleven of these trials compared inhaled antibiotics with placebo (an inhaled substance without the medication in it) and people were selected for one treatment or the other randomly. Eight of the trials compared one inhaled antibiotic with either a different inhaled antibiotic or a different schedule of the same inhaled antibiotic. One of the trials compared an antibiotic to placebo as well as to a different antibiotic and so fell into both groups.

Key results

Results from four trials showed that when compared to placebo, inhaled antibiotics improved lung function and reduced the number of times the people with cystic fibrosis had a worsening of symptoms (exacerbation). We did not find enough evidence to be able to comment on how these antibiotics affect quality of life, height and weight, or survival.

Where the trials compared different inhaled antibiotics, there was only one trial in each of the eight comparisons. In one trial we found that aztreonam improved lung function more than tobramycin, but no important differences were found in the other trials with regard to lung function.

Important side effects that were related to the treatment were not very common in the trials, but they were less common with tobramycin than with other antibiotics.

Quality of the evidence

The trials that we included in this review were very different in the way that they measured how well the lungs work after treatment and how often people experienced a sudden worsening of symptoms. That made it difficult for us to combine the results of different trials to strengthen our evidence. We thought the overall quality of evidence was low for most outcomes, mainly due to risks of bias within the trials and low event rates meaning results were not precise.

Authors' conclusions: 

Inhaled anti-pseudomonal antibiotic treatment probably improves lung function and reduces exacerbation rate, but pooled estimates of the level of benefit were very limited. The best evidence is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes.

Read the full abstract...
Background: 

Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review.

Objectives: 

To evaluate the effects long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug sensitivity reactions and survival).

Search strategy: 

We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries.

Date of last search: 13 February 2018.

Selection criteria: 

We selected trials if inhaled anti-pseudomonal antibiotic treatment was used for at least three months in people with cystic fibrosis, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic).

Data collection and analysis: 

Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the quality of the evidence using the GRADE system.

Main results: 

The searches identified 333 citations to 98 trials; 18 trials (3042 participants aged between five and 56 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One of the trials (18 participants) compared to placebo and a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials.

We found limited evidence that inhaled antibiotics improved lung function (four of the 11 placebo-controlled trials, n = 814). Compared to placebo, inhaled antibiotics also reduced the frequency of exacerbations (three trials, n = 946), risk ratio 0.66 (95% confidence interval (CI) 0.47 to 0.93). There were insufficient data for us to be able to report an effect on nutritional outcomes or survival and there were insufficient data for us to ascertain the effect on quality of life. There was no significant effect on antibiotic resistance seen in the two trials that were included in meta-analyses. Tinnitus and voice alteration were the only adverse events significantly more common in the inhaled antibiotics group. The overall quality of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates.

Of the eight trials that compared different inhaled antibiotics or different antibiotic regimens, there was only one trial in each comparison. Forced expiratory volume at one second (FEV1) % predicted was only found to be significantly improved with aztreonam lysine for inhalation compared to tobramycin (n = 273), mean difference -3.40% (95% CI -6.63 to -0.17). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. No significant differences were found in the remaining comparisons with regard to lung function. Pulmonary exacerbations were measured in different ways, but one trial (n = 273) found that the number of people treated with antibiotics was lower in those receiving aztreonam than tobramycin, risk ratio 0.66 (95% CI 0.51 to 0.86). We found the quality of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high.

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