- Cystic fibrosis (CF) is an inherited condition where the airways often become blocked with mucus, and people with CF are more likely to get chest infections which cause more damage to the lungs.
- Pseudomonas aeruginosa (P aeruginosa) is often the cause of infection and is difficult to get rid of; antibiotics are the main treatment, but there are many different antibiotics, and they can be given in different ways.
- Inhaled antibiotics may be better than no treatment allowing most people to remain free of P aeruginosa after one month.
- There seems to be little difference in the other treatments we compared regarding how well they clear P aeruginosa from the lungs.
What is cystic fibrosis?
CF is the most common inherited condition that is life-limiting. Sticky mucus builds up in the lungs of people with CF, which makes it difficult to breathe and can lead to chest infections. These chest infections can cause further lung damage and lead to breathing failure and death. A germ called P aeruginosa is often the cause of infection and is difficult to treat successfully, once it has persisted for longer than six months.
What did we want to find out?
We wanted to compare different combinations of inhaled, oral and intravenous (IV) antibiotics for clearing P aeruginosa in people with CF, to see if any single treatment works best and is more cost-effective.
What did we find?
The review includes 11 studies with a total of 1449 people with CF, of any age or sex, who had mild to severe lung disease. The studies lasted from 28 days to 27 months. We could not combine many results as studies used different treatments. There were 10 different comparisons of antibiotic treatments: three studies compared inhaled antibiotics with a placebo (dummy treatment); two studies compared inhaled antibiotics for different lengths of time; two studies compared inhaled tobramycin with or without oral antibiotics depending on how the infection was detected; two studies compared inhaled antibiotics plus an oral antibiotic with inhaled antibiotics plus a placebo; one study compared two different inhaled antibiotics plus an oral antibiotic; and one study compared IV antibiotics with oral antibiotics.
Most of the studies showed how well the treatments got rid of P aeruginosa as well as how they affected lung function, other germs, worsening of flare-ups, and side effects.
Three small studies (of 89 people) treating early infection showed that after one month, inhaled antibiotics were better than no treatment and cleared P aeruginosa in most people, but our confidence in the evidence is low.
There is likely to be little difference in the other treatments regarding how well they clear P aeruginosa from the lungs, although we found that inhaled antibiotics, alone or with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. A study of IV ceftazidime with tobramycin in comparison with oral ciprofloxacin also showed neither group was better at getting rid of P aeruginosa, but we are more certain of the results and this means that it may be just as effective to treat with oral antibiotics.
What are the limitations of the evidence?
Some studies were carried out up to 30 years ago and the results may not apply today, and some studies were small. Most studies were quite short, so we could not show whether treatment made people with CF feel better or live longer. Given the treatments used in most of the studies, it would have been easy for people to guess which treatment they were receiving, which might have influenced some of the results. Two studies were supported by the pharmaceutical industry. Further research is needed to see whether clearing the infection completely improves the well-being and quality of life in people with CF and to establish which antibiotic combination is best at clearing P aeruginosa.
Overall our confidence in the evidence was moderate to very low, so further research is likely to change our confidence in the results. However, we have higher confidence in one recently published study, which means we can be more sure of the results.
How up to date is this evidence?
The studies we have reported on are the most up-to-date we could find. We last searched the literature in April 2022.
We found that nebulised antibiotics, alone or with oral antibiotics, were better than no treatment for early infection with P aeruginosa. Eradication may be sustained in the short term. There is insufficient evidence to determine whether these antibiotic strategies decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of P aeruginosa. One large trial showed that intravenous ceftazidime with tobramycin is not superior to oral ciprofloxacin when inhaled antibiotics are also used. There is still insufficient evidence to state which antibiotic strategy should be used for the eradication of early P aeruginosa infection in CF, but there is now evidence that intravenous therapy is not superior to oral antibiotics.
Respiratory tract infections with Pseudomonas aeruginosa occur in most people with cystic fibrosis (CF). Established chronic P aeruginosa infection is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate.
This is an updated review.
Does giving antibiotics for P aeruginosa infection in people with CF at the time of new isolation improve clinical outcomes (e.g. mortality, quality of life and morbidity), eradicate P aeruginosa infection, and delay the onset of chronic infection, but without adverse effects, compared to usual treatment or an alternative antibiotic regimen? We also assessed cost-effectiveness.
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings. Latest search: 24 March 2022.
We searched ongoing trials registries. Latest search: 6 April 2022.
We included randomised controlled trials (RCTs) of people with CF, in whom P aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous (IV) antibiotics with placebo, usual treatment or other antibiotic combinations. We excluded non-randomised trials and cross-over trials.
Two authors independently selected trials, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE.
We included 11 trials (1449 participants) lasting between 28 days and 27 months; some had few participants and most had relatively short follow-up periods. Antibiotics in this review are: oral – ciprofloxacin and azithromycin; inhaled – tobramycin nebuliser solution for inhalation (TNS), aztreonam lysine (AZLI) and colistin; IV – ceftazidime and tobramycin. There was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment. Two trials were supported by the manufacturers of the antibiotic used.
TNS versus placebo
TNS may improve eradication; fewer participants were still positive for P aeruginosa at one month (odds ratio (OR) 0.06, 95% confidence interval (CI) 0.02 to 0.18; 3 trials, 89 participants; low-certainty evidence) and two months (OR 0.15, 95% CI 0.03 to 0.65; 2 trials, 38 participants). We are uncertain whether the odds of a positive culture decrease at 12 months (OR 0.02, 95% CI 0.00 to 0.67; 1 trial, 12 participants).
TNS (28 days) versus TNS (56 days)
One trial (88 participants) comparing 28 days to 56 days TNS treatment found duration of treatment may make little or no difference in time to next isolation (hazard ratio (HR) 0.81, 95% CI 0.37 to 1.76; low-certainty evidence).
Cycled TNS versus culture-based TNS
One trial (304 children, one to 12 years old) compared cycled TNS to culture-based therapy and also ciprofloxacin to placebo. We found moderate-certainty evidence of an effect favouring cycled TNS therapy (OR 0.51, 95% CI 0.31 to 0.82), although the trial publication reported age-adjusted OR and no difference between groups.
Ciprofloxacin versus placebo added to cycled and culture-based TNS therapy
One trial (296 participants) examined the effect of adding ciprofloxacin versus placebo to cycled and culture-based TNS therapy. There is probably no difference between ciprofloxacin and placebo in eradicating P aeruginosa (OR 0.89, 95% CI 0.55 to 1.44; moderate-certainty evidence).
Ciprofloxacin and colistin versus TNS
We are uncertain whether there is any difference between groups in eradication of P aeruginosa at up to six months (OR 0.43, 95% CI 0.15 to 1.23; 1 trial, 58 participants) or up to 24 months (OR 0.76, 95% CI 0.24 to 2.42; 1 trial, 47 participants); there was a low rate of short-term eradication in both groups.
Ciprofloxacin plus colistin versus ciprofloxacin plus TNS
One trial (223 participants) found there may be no difference in positive respiratory cultures at 16 months between ciprofloxacin with colistin versus TNS with ciprofloxacin (OR 1.28, 95% CI 0.72 to 2.29; low-certainty evidence).
TNS plus azithromycin compared to TNS plus oral placebo
Adding azithromycin may make no difference to the number of participants eradicating P aeruginosa after a three-month treatment phase (risk ratio (RR) 1.01, 95% CI 0.75 to 1.35; 1 trial, 91 participants; low-certainty evidence); there was also no evidence of any difference in the time to recurrence.
Ciprofloxacin and colistin versus no treatment
A single trial only reported one of our planned outcomes; there were no adverse effects in either group.
AZLI for 14 days plus placebo for 14 days compared to AZLI for 28 days
We are uncertain whether giving 14 or 28 days of AZLI makes any difference to the proportion of participants having a negative respiratory culture at 28 days (mean difference (MD) -7.50, 95% CI -24.80 to 9.80; 1 trial, 139 participants; very low-certainty evidence).
Ceftazidime with IV tobramycin compared with ciprofloxacin (both regimens in conjunction with three months colistin)
IV ceftazidime with tobramycin compared with ciprofloxacin may make little or no difference to eradication of P aeruginosa at three months, sustained to 15 months, provided that inhaled antibiotics are also used (RR 0.84, 95 % CI 0.65 to 1.09; P = 0.18; 1 trial, 255 participants; high-certainty evidence). The results do not support using IV antibiotics over oral therapy to eradicate P aeruginosa, based on both eradication rate and financial cost.