Review question
Are inhaled antibiotics helpful against persistent infection with Pseudomonas aeruginosa in people with cystic fibrosis (CF)?
Key messages
As people with CF 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 breathed 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.
What is CF?
Cystic fibrosis is an inherited disease which results in abnormal mucus in several parts of the body and mainly affects the lungs, which are susceptible to infection by certain bacteria. Infection causes inflammation which results in progressive damage to the lungs.
What did we find?
The review includes 18 trials with 3042 people with CF aged between five and 45 years of age. The trials lasted from three to 33 months. In 11 trials investigators compared inhaled antibiotics with a placebo (an inhaled substance without the medication in it) and people were selected for one treatment or the other randomly. Eight 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 both to placebo and to a different antibiotic and so fell into both groups.
Main results
Results from four trials showed that when compared to placebo, inhaled antibiotics may improve lung function and reduce the number of times the people with CF had a worsening of symptoms (exacerbation). Inhaled antibiotics may also mean fewer days off school or work (a measure of quality of life). They did not seem to have an effect on survival. We are not sure of the side effects of inhaled antibiotics, but tinnitus and changes in voice were reported more often in people inhaling antibiotics rather than the placebo. We did not find enough evidence to be able to comment on how inhaled antibiotics affect height and weight.
Where the trials compared different inhaled antibiotics or schedules, there was only one trial in each of the eight different comparisons. The only differences we found in all these comparisons were for two outcomes. In one trial we found that aztreonam lysine probably improved lung function more than tobramycin, but no important differences were found in the other trials with regard to lung function. Aztreonam lysine also probably led to fewer people needing additional courses of antibiotics than tobramycin and there were fewer hospitalisations after levofloxacin compared to placebo. We noted that 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.
What are the limitations of the evidence?
The trials that we included in this review measured lung function in different ways and also 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 certainty 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.
How up to date is this evidence?
The evidence is current to: 28 June 2022.
Long-term treatment with inhaled anti-pseudomonal antibiotics probably improves lung function and reduces exacerbation rates, but pooled estimates of the level of benefit were very limited. The best evidence available 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.
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.
To evaluate the effects of 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).
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: 28 June 2022.
We selected trials where people with cystic fibrosis received inhaled anti-pseudomonal antibiotic treatment for at least three months, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic).
Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the certainty of the evidence using the GRADE system.
The searches identified 410 citations to 125 trials; 18 trials (3042 participants aged between five and 45 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 trial (18 participants) compared an antibiotic to placebo and also to a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials.
Inhaled antibiotics compared to placebo
We found that inhaled antibiotics may improve lung function measured in a variety of ways (4 trials, 814 participants). Compared to placebo, inhaled antibiotics may also reduce the frequency of exacerbations (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.47 to 0.93; 3 trials, 946 participants; low-certainty evidence). Inhaled antibiotics may lead to fewer days off school or work (quality of life measure) (mean difference (MD) -5.30 days, 95% CI -8.59 to -2.01; 1 trial, 245 participants; low-certainty evidence). There were insufficient data for us to be able to report an effect on nutritional outcomes and there was no effect on survival. There was no effect on antibiotic resistance seen in the two trials that were included in meta-analyses. We are uncertain of the effect of the intervention on adverse events (very low-certainty evidence), but tinnitus and voice alteration were the only events occurring more often in the inhaled antibiotics group. The overall certainty 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.
Different antibiotics or regimens compared
Of the eight trials comparing different inhaled antibiotics or different antibiotic regimens, there was only one trial for each unique comparison. We found no differences between groups for any outcomes except for the following. Aztreonam lysine for inhalation probably improved forced expiratory volume at one second (FEV1) % predicted compared to tobramycin (MD -3.40%, 95% CI -6.63 to -0.17; 1 trial, 273 participants; moderate-certainty evidence). 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. We found no differences in any measure of lung function in the remaining comparisons. Trials measured pulmonary exacerbations in different ways and showed no differences between groups except for aztreonam lysine probably leading to fewer people needing treatment with additional antibiotics than with tobramycin (RR 0.66, 95% CI 0.51 to 0.86; 1 trial, 273 participants; moderate-certainty evidence); and there were fewer hospitalisations due to respiratory exacerbations with levofloxacin compared to tobramycin (RR 0.62, 95% CI 0.40 to 0.98; 1 trial, 282 participants; high-certainty evidence). Important treatment-related adverse events were not very common across comparisons, but were reported less often in the tobramycin group compared to both aztreonam lysine and colistimethate. We found the certainty of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high.