Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis

Abstract

Background

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.

Objectives

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.

Search methods

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.

Selection criteria

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.

Data collection and analysis

Two authors independently selected trials, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE.

Main results

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.

Authors' conclusions

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.

Plain language summary

Different ways of giving antibiotics to clear Pseudomonas aeruginosa infection in people with cystic fibrosis

Key messages

‐ 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.

Main results

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.

Summary of findings

Summary of findings 1. Inhaled tobramycin (TNS) compared with placebo.

Inhaled tobramycin (TNS) compared with placebo for eradicating Pseudomonas aeruginosa in people with cystic fibrosis
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of Pseudomonas aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: TNS Comparison: placebo
Outcomes		Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (trials)	Certainty of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		Placebo	TNS
Eradication of P aeruginosa from the respiratory tract: proportion with positive respiratory culture for P aeruginosa Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months (1 month)	787 per 1000	182 per 1000 (69 to 400 per 1000)	OR 0.06 (95% CI 0.02 to 0.18)	89 (3 RCTs)	⊕⊕⊝⊝ lowa,b	The included trials gave very different doses of TNS (80 mg or 300 mg 2 x daily).
	Follow‐up: 6 to 24 months after onset of treatment (12 months)	OR 0.02 (95% CI 0.00 to 0.67)		OR 0.02 (95% CI 0.00 to 0.67)	12 (1 RCT)	⊕⊝⊝⊝ very lowa,b,c	We were unable to calculate assumed and corresponding risk as all the participants in the placebo group had a positive respiratory culture at 12 months. Results of different time points and sensitivity analyses to account for missing data in 1 trial were variable, showing no consistent advantage to TNS over placebo.
FEV1 Follow‐up: up to 2 years		There were no changes in spirometric pulmonary function during or after the treatment period.		NR	up to 22d (1 RCT)	⊕⊝⊝⊝ very lowa,b,e	No numerical data were reported.
FVC Follow‐up: up to 2 years		There were no changes in spirometric pulmonary function during or after the treatment period.		NR	up to 22d (1 RCT)	⊕⊝⊝⊝ very lowa,b,e	No numerical data were reported.
Growth and nutritional status: change in weight (kg) from baseline Follow‐up: up to 2 years		Outcome not reported at specified time point (see comments).					There was no difference in the mean change in weight from baseline between groups at 1 month (MD 0.20 kg, 95% CI ‐0.28 to 0.68) or 2 months (0.1 kg, 95% CI ‐0.38 to 0.58).
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year		Outcome not reported.
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year Follow‐up: up to 2 years		Outcome not reported at specified time point (see comments)					No numerical data were reported. At the 2‐month time point, there were no changes in the prevalence of other micro‐organisms, including multiresistant organisms, cultured from respiratory secretions.
Adverse effects of antibiotics: participants experiencing cough Follow‐up: up to 2 years		342 per 1000	283 per 1000 (49 to 750)	OR 0.76 (0.10 to 5.77)	72 (2 RCTs)	⊕⊝⊝⊝ very lowa,b,c	No other specific adverse events were reported. The trial reporting at 2 months found no difference between groups with regard to cough (OR 0.58, 95% CI 0.03 to 10.86), serum creatinine levels or auditory threshold at the 2‐month time point.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; MD: mean difference; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa; RCT: randomised controlled trial; TNS: inhaled tobramycin
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aDowngraded once due to risk of bias; methodological information was limited and unclear in the included trials and there were concerns regarding incomplete outcome data, selective reporting and other biases due to the early termination of one trial.
^bDowngraded once due to applicability: the included trials recruited only children; results are not applicable to adults.
^cDowngraded once due to imprecision caused by very small sample size and wide CIs.
^dIn the included trial, 22 participants were randomised, but it is not clear if all participants contributed to this outcome.
^eDowngraded once due to imprecision: no numerical results available.

Summary of findings 2. Inhaled tobramycin (TNS) (28 days) compared with TNS (56 days).

Inhaled tobramycin (TNS) (28 days) compared with TNS (56 days) for eradicating Pseudomonas aeruginosa in people with cystic fibrosis
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: TNS (28 days) Comparison: TNS (56 days)
Outcomes		Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		TNS (56 days)	TNS (28 days)
Eradication of P aeruginosa from the respiratory tract: time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	Not reported at this time point
	Follow‐up: 6 to 24 months after onset of treatment	By 26.12 months, 50% of people in the 56‐day group can expect to have experienced a recurrence of P aeruginosa.	By 25.18 months, 50% of people in the 28‐day group can expect to have experienced a recurrence of P aeruginosa.	HR 0.81 (95% CI 0.37 to 1.76)	65a (1 RCT)	⊕⊕⊝⊝ lowb,c
FEV1: % predicted Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		There were no major short‐ or long‐term changes in spirometric parameters were observed during the trial period.		NR	up to 88a (1 RCT)	⊕⊝⊝⊝ very lowb,c,d	Changes in lung function were not reported separately for each treatment arm.
FVC: % predicted Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		There were no major short‐ or long‐term changes in spirometric parameters were observed during the trial.		NR	up to 88a (1 RCT)	⊕⊝⊝⊝ very lowb,c,d	Changes in lung function were not reported separately for each treatment arm.
Growth and nutritional status: weight, height and BMI Follow‐up: 6 to 24 months		No differences in weight, height or body mass index were reported.		NR	up to 88a (1 RCT)	⊕⊝⊝⊝ very lowb,c,d	Numerical data were not reported or comparative results across the treatment groups.
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		47 per 1000	9 per 1000 (0 to 188 per 1000)	OR 0.19 (95% CI 0.01 to 4.00)	77a (1 RCT)	⊕⊝⊝⊝ very lowb,c,e
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		There were no consistent trends reported in the isolation of non‐P aeruginosa organisms (one isolate only of Stenotrophomonas maltophilia, which was seen in the 28‐day arm).		NR	up to 88a (1 RCT)	⊕⊝⊝⊝ very lowb,c,d	Numerical data were not reported, or comparative results across the treatment groups.
Adverse effects of antibiotics Follow‐up: 6 to 24 months (N.B. this trial reported at 27 months)		There were no differences between treatment groups in terms of any reported adverse events at any time point.		NA	up to 77a (1 RCT)	⊕⊝⊝⊝ very lowb,c,f
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BAL: bronchial lavage CI: confidence interval; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; HR: hazard ratio; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aIn the included trial, 88 participants were randomised but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes).
^bDowngraded once due to risk of bias; methodological information was limited and unclear in the included trial and there were concerns of bias due to selective reporting of results and lack of blinding.
^cDowngraded once due to applicability: the included trials recruited only children; results are not applicable to adults.
^dDowngraded once due to imprecision: no numerical comparative results available.
^eDowngraded once due to imprecision: very wide CIs around the effect size
^fDowngraded once due to imprecision: some wide confidence intervals around effects sizes (small event rates) and a lot of adverse events analysed increasing the statistical chance of a spurious finding.

Summary of findings 3. Cycled inhaled tobramycin (TNS) compared to culture‐based TNS.

Cycled inhaled tobramycin (TNS) compared to culture‐based TNS for eradicating Pseudomonas aeruginosa in people with cystic fibrosis
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: cycled TNS Comparison: culture‐based TNS
Outcomes		Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		Culture‐based inhaled tobramycin	Cycled inhaled tobramycin
Eradication of P aeruginosa from the respiratory tract: proportion of participants with one or more isolates of P aeruginosa from the respiratory tract Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	Outcome not reported at this time point.
	Follow‐up: 6 to 24 months after onset of treatment	467 per 1000	228 per 1000 (145 to 383 per 1000)	OR 0.51 (95% CI 0.31 to 0.82)	298a (1 RCT)	⊕⊕⊕⊝ moderateb	The original trial report published age group–adjusted ORs, which are slightly different to the results of this review.
FEV1: mean 70‐week % change in FEV1 (% predicted) Follow‐up: 70 weeks		The mean 70‐week % change in FEV1 (% predicted) was ‐1.61% in the culture‐based TNS group.	The mean 70‐week % change in FEV1 (% predicted) was 2.38% higher (2% lower to 6.76% higher) in the cycle‐based TNS group.	NA	143a (1 RCT)	⊕⊕⊝⊝ lowb,c
FVC		Outcome not reported.		NA	NA	NA
Growth and nutritional status: mean 70‐week change from baseline in weight (kg) and height (cm) Follow‐up: 70 weeks		The mean 70‐week change in weight (kg) in the culture‐based group was 3.9kg. Change in weight in the cycled group was 0.10kg higher (0.47 lower to 0.67 higher). The mean 70‐week change in height (cm) in the culture‐based group was 9.4cm. Change in height in the cycled group was 0.20cm lower (0.86 lower to 0.46 higher).		NA	304a (1 RCT)	⊕⊕⊕⊝ moderateb
Frequency of infective pulmonary exacerbations: proportion of participants with one or more pulmonary exacerbations (any severity) Follow‐up: 18 months		533 per 1000	400 per 1000 (256 to 624 per 1000)	OR 0.75 (95% 0.48 to 1.17)	304a (1 RCT)	⊕⊕⊕⊝ moderateb	There was also no difference between groups in terms of proportion of participants with 1 or more severe pulmonary exacerbation or in terms of time to pulmonary exacerbation (severe or any severity).
Isolation of other micro‐organisms from the respiratory tract: proportion of participants with new isolates of Stenotrophomonas maltophilia Follow‐up: 18 months		184 per 1000	217 per 1000 (118 to 390 per 1000)	OR 1.18 (95% CI 0.65 to 2.12)	279a (1 RCT)	⊕⊕⊕⊝ moderateb
Adverse effects of antibiotics: proportion of participants with one or more serious adverse events Follow‐up: 18 months		289 per 1000	246 per 1000 (147 to 405 per 1000)	OR 0.85 (95% 0.51 to 1.40)	304a (1 RCT)	⊕⊕⊕⊝ moderateb
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aIn the included trial, 306 participants were randomised, 304 received treatment but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes, spirometry not performed in very young children (less than 4 years of age)).
^bDowngraded once due to applicability: the included trial recruited only children; results are not applicable to adults. Also, the included trial required participants to have been free of P aeruginosa for at least 2 years, so results may not be applicable to a wider population.
^cDowngraded once due to applicability: a large proportion of the randomised and treated participants (161 out of 304, 53%) did not contribute to this outcome.

Summary of findings 4. Ciprofloxacin compared to placebo added to cycled and culture‐based inhaled tobramycin (TNS) therapy.

Ciprofloxacin compared to placebo added to cycled and culture‐based inhaled tobramycin (TNS) therapy for eradicating Pseudomonas aeruginosa in people with cystic fibrosis
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: ciprofloxacin added to cycled and culture‐based TNS therapy Comparison: placebo added to cycled and culture‐based TNS therapy
Outcomes		Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		Placebo added to cycled and culture‐based TNS therapy	Ciprofloxacin added to cycled and culture‐based TNS therapy
Eradication of P aeruginosa from the respiratory tract: proportion of participants with one or more isolates of P aeruginosa from the respiratory tract Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	Outcome not reported at this time point.
	Follow‐up: 6 to 24 months after onset of treatment	362 per 1000	322 per 1000 (199 to 521 per 1000)	OR 0.89 (95% CI 0.55 to 1.44)	298a (1 RCT)	⊕⊕⊕⊝ moderateb	The original trial report published age group‐adjusted ORs, which are slightly different to the results of this review.
FEV1: mean 70‐week % change in FEV1 (% predicted) Follow‐up: 70 weeks		The mean 70‐week % change in FEV1 (% predicted) was ‐1.85% in the placebo added to cycled and culture‐based TNS therapy group.	The mean 70‐week % change in FEV1 (% predicted) was 3.02% higher (1.33% lower to 7.37% higher) in the ciprofloxacin added to cycled and culture‐based TNS therapy group.	NA	143a (1 RCT)	⊕⊕⊝⊝ lowb,c
FVC		Outcome not reported.		NA	NA	NA
Growth and nutritional status: mean 70‐week change from baseline in weight (kg) and height (cm) Follow‐up: 70 weeks		The mean 70‐week change in weight (kg) in the placebo added to cycled and culture‐based therapy group was 4.10 kg. Change in weight in the cycled group was 0.30 kg lower (0.88 lower to 0.28 higher). The mean 70‐week change in height (cm) in the placebo added to cycled and culture‐based therapy group was 9.4 cm. Change in height in the cycled group was 0.20 cm lower (0.86 lower to 0.46 higher).		NA	304a (1 RCT)	⊕⊕⊕⊝ moderateb
Frequency of infective pulmonary exacerbations: proportion of participants with one or more pulmonary exacerbations (any severity) Follow‐up: 18 months		447 per 1000	666 per 1000 (425 to 1000)	OR 1.49 (95% CI 0.95 to 2.33)	304a (1 RCT)	⊕⊕⊕⊝ moderateb	There was also no difference between groups in the proportion of participants with 1 or more severe pulmonary exacerbations or in the time to pulmonary exacerbation (severe or any severity).
Isolation of other micro‐organisms from the respiratory tract: proportion of participants with new isolates of Stenotrophomonas maltophilia Follow‐up: 18 months		183 per 1000	220 per 1000 (121 to 395 per 1000)	OR 1.20 (95% CI 0.66 to 2.16)	279a (1 RCT)	⊕⊕⊕⊝ moderateb
Adverse effects of antibiotics: proportion of participants with one or more serious adverse event Follow‐up: 18 months		230 per 1000	354 per 1000 (214 to 591 per 1000)	OR 1.54 (95% CI 0.93 to 2.57)	304a (1 RCT)	⊕⊕⊕⊝ moderateb
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; NA: not applicable; NR: not reported; OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aIn the included trial, 306 participants were randomised, 304 received treatment but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes, spirometry not performed in very young children (less than 4 years of age)).
^bDowngraded once due to applicability: the included trial recruited only children; results are not applicable to adults. Also, the included trial required participants to have been free of P aeruginosa for at least 2 years, so results may not be applicable to a wider population.
^cDowngraded once due to applicability: a large proportion of the randomised and treated participants (161 out of 304, 53%) did not contribute to this outcome.

Summary of findings 5. Oral ciprofloxacin and inhaled colistin compared to inhaled tobramycin (TNS).

Oral ciprofloxacin and inhaled colistin compared to inhaled tobramycin for eradicating Pseudomonas aeruginosa in people with cystic fibrosis
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: oral ciprofloxacin and inhaled colistin Comparison: TNS
Outcomes		Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		TNS	Oral ciprofloxacin and inhaled colistin
Eradication of P aeruginosa from the respiratory tract: proportion with positive respiratory culture for P aeruginosa Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	552 per 1000	346 per 1000	OR 0.43 (95% CI 0.15 to 1.23)	Up to 58a (1 RCT)	⊕⊝⊝⊝ very lowb,c,d
	Follow‐up: 6 to 24 months after onset of treatment	458 per 1000	348 per 1000 (110 to 1000 per 1000)	OR 0.76 (95% CI 0.24 to 2.42)	Up to 58a (1 RCT)	⊕⊝⊝⊝ very lowb,c,d
FEV1: change from baseline (% predicted) Follow‐up: over 6 months and up to 24 months		Median change from baseline in FEV1 (% predicted) for all the participants was ‐1%.		NR	Up to 58a (1 RCT)	⊕⊝⊝⊝ very lowb,c,e	Changes in FEV1 were not reported separately for each treatment arm.
FVC Follow‐up: NA		Outcome not reported.		NA	NA	NA
Growth and nutritional status: BMI and weight z score Follow‐up: 6 to 24 months		Both BMI z score and weight z score were reported not to have changed significantly for trial participants as a whole.		NR	Up to 58a (1 RCT)	⊕⊝⊝⊝ very lowb,c,e	Numerical data were not reported for comparative results across the treatment groups.
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year Follow‐up: over 6 months and up to 24 months		During the first 6 months of follow‐up, there was no difference between the 2 treatment arms in number of oral antibiotic treatment days.		NR	Up to 58a (1 RCT)	⊕⊝⊝⊝ very lowb,c,e	These oral antibiotics were given for symptoms and not because of failed eradication. No numerical data were reported.
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year Follow‐up: NA		Outcome not reported.		NA	NA	NA
Adverse effects of antibiotics: severe cough Follow‐up: over 6 months and up to 24 months		34 per 1000	11 per 1000 (0 to 280 per 1000)	OR 0.32 (95% CI 0.01 to 8.24)	Up to 58a (1 RCT)	⊕⊝⊝⊝ very lowb,c,d	No other specific adverse events were reported.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMI: body mass index; CI: confidence interval; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aIn the included trial, 58 participants were randomised but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes).
^bDowngraded once due to risk of bias; methodological information was limited and unclear in the included trial and there were concerns of bias due to selective reporting of results.
^cDowngraded once due to applicability: the included trials recruited only children; results are not applicable to adults.
^dDowngraded once due to imprecision: very wide CIs around the effect size.
^eDowngraded once due to imprecision: no numerical comparative results available.

Summary of findings 6. Inhaled colistin plus oral ciprofloxacin compared to inhaled tobramycin (TNS) plus oral ciprofloxacin.

Inhaled colistin plus oral ciprofloxacin compared to inhaled tobramycin (TNS) plus oral ciprofloxacin for eradicating Pseudomonas aeruginosa in people with cystic fibrosis
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: inhaled colistin plus oral ciprofloxacin Comparison: TNS plus oral ciprofloxacin
Outcomes		Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		TNS plus oral ciprofloxacin	Inhaled colistin plus oral ciprofloxacin
Eradication of P aeruginosa from the respiratory tract: proportion with positive respiratory culture for P aeruginosa Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	347 per 1000	371 per 1000 (254 to 506	OR 1.11 (95% CI 0.64 to 1.92)	Up to 223a (1 RCT)	⊕⊕⊝⊝ lowb,c
	Follow‐up: 6 to 24 months after onset of treatment (median 16 months)	315 per 1000	403 per 1000 (227 to 721 per 1000)	OR 1.28 (95% CI 0.72 to 2.29)	Up to 223a (1 RCT)	⊕⊕⊝⊝ lowb,c
FEV1: relative change in % predicted FEV1 from baseline		Outcome not reported at specified time point.					After a mean time of 54 days there was no difference in mean relative change in FEV1 % predicted between groups, MD ‐2.40 (95% CI ‐5.89 to 1.09)
FVC Follow‐up: NA		Outcome not reported.
Growth and nutritional status Follow‐up: NA		Outcome not reported.
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year Follow‐up: NA		Outcome not reported.
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year Follow‐up: median 16 months		There were no differences during follow‐up between the two groups for isolation of: Stenotrophomonas maltophilia (OR 0.89 (95% CI 0.45 to 1.78)) ,Achromobacter xylosoxidans (OR 1.53 (95% CI 0.51 to 4.57))or Aspergillus species (OR 0.48 (95% CI 0.21 to 1.07)).		NA	205a (1 RCT)	⊕⊕⊕⊝ moderateb
Adverse effects of antibiotics: leading to trial discontinuation Follow‐up: median 16 months		21 out of 118 (18%) participants discontinued the trial early due to adverse events in the TNS plus oral ciprofloxacin group.	17 out of 105 (16%) participants discontinued the trial early due to adverse events in the inhaled colistin plus oral ciprofloxacin group.	NA	223 (1 RCT)	⊕⊕⊕⊝ moderateb	Reasons for discontinuations included vomiting, photosensitivity, wheeze and pulmonary exacerbation.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; NA: not applicable; NR: not reported OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa; RCT: randomised controlled trial; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aIn the included trial, 223 participants were randomised but not all participants contributed to all outcomes (unclear how many participants contributed to some outcomes, spirometry not performed in very young children).
^bDowngraded once due to risk of bias; methodological information was limited and unclear in the included trial and there were potential concerns of bias due to selective reporting of results and lack of blinding.
^cDowngraded once due to imprecision: wide CIs around the effect size.

Summary of findings 7. Inhaled tobramycin (TNS) plus oral azithromycin compared to TNS plus oral placebo.

Inhaled tobramycin (TNS) plus oral azithromycin compared to TNS plus oral placebo for eradicating Pseudomonas aeruginosa in people with cystic fibrosis
Patient or population: children with cystic fibrosis and a new culture positive for P aeruginosa Settings: outpatients Intervention: TNS plus oral azithromycin Comparison: TNS plus oral placebo
Outcomes		Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		TNS plus placebo	TNS plus azithromycin
Eradication of P aeruginosa from the respiratory tract: number of participants eradicated after three month treatment phase Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months (3 months)	667 per 1000	674 per 1000 (500 to 900 per 1000)	RR 1.01 (0.75 to 1.35)	91 (1 RCT)	⊕⊕⊝⊝ lowa,b	This included participants who were positive for P aeruginosa at baseline and had a culture result available at the end of the first treatment quarter.
	Follow‐up: 6 to 24 months after onset of treatment	Outcome not reported at this time point.
FEV1: mean change in FEV1 % predicted Follow‐up: 18 months		There was no difference in the mean change in FEV1 over the 18‐month period between groups, MD ‐1.71% (‐7.76 to 4.34).			132 (1 RCT)	⊕⊕⊝⊝ lowa,b	P = 0.384 Results taken directly from paper.
FVC: mean change in FVC % predicted Follow‐up: 18 months		There was no difference in the mean change in FVC over the 18‐month period between groups.				⊕⊕⊝⊝ lowa,b	No data are available for this outcome.
Growth and nutritional status: mean change in weight (kg) from baseline Follow‐up: 18 months		There was a slight improvement in weight in the azithromycin group compared to the placebo group, MD 1.27 (0.01 to ‐2.52)			221 (1 RCT)	⊕⊕⊕⊝ moderateb	P = 0.046 Results taken directly from paper.
Frequency of infective pulmonary exacerbations: number of participants experiencing an exacerbation by the end of the study Follow‐up: 18 months		522 per 1000	392 per 1000 (292 to 522 per 1000)	RR 0.75 (0.56 to 1.00)	221 (1 RCT)	⊕⊕⊕⊝ moderateb
Isolation of other micro‐organisms from the respiratory tract: number of participants with a positive result for other organisms. Follow‐up: 18 months		The emergence of other pathogens (including A xylosoxidans, B cepacia, H influenzae, S aureus, S maltophilia and NTM) was comparable between groups and numbers were low.			221 (1 RCT)	⊕⊕⊕⊝ moderateb	The analysis included participants with a positive result who were negative at baseline.
Adverse effects of antibiotics: number of participants experiencing any adverse event Follow‐up: 18 months		883 per 1000	927 per 1000 (848 to 1000 per 1000)	RR 1.05 (0.96 to 1.14)	221 (1 RCT)	⊕⊕⊕⊝ moderateb	There was no difference between groups in the occurrence of adverse events, including serious adverse events.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). A xylosoxidans: Achromobacter xylosoxidans;B cepacia: Burkholderia cepacia; CI: confidence interval; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; H influenzae: Haemophilus influenzae; MD: mean difference; NA: not applicable; NR: not reported; NTM: nontuberculous mycobacterium; OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa; RCT: randomised controlled trial; RR: risk ratio; S aureus: Staphylococcus aureus; S maltophilia: Stenotrophomonas maltophilia; TNS: inhaled tobramycin.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aDowngraded once due to imprecision: small number of participants.
^bDowngraded once due to indirectness: the included trial recruited only children; results are not applicable to adults.

Summary of findings 8. Oral ciprofloxacin and inhaled colistin compared with no treatment.

Oral ciprofloxacin and inhaled colistincompared with no treatment for eradicating Pseudomonas aeruginosa in people with cystic fibrosis
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of P aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: oral ciprofloxacin and inhaled colistin Comparison: no treatment
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	No treatment	Oral ciprofloxacin and inhaled colistin
Eradication of P aeruginosa from the respiratory tract	Outcome not reported.
FEV1	Outcome not reported.
FVC	Outcome not reported.
Growth and nutritional status	Outcome not reported.
Frequency of infective pulmonary exacerbations: number of exacerbations per patient year	Outcome not reported.
Isolation of other micro‐organisms from the respiratory tract: number of positive cultures per patient year	Outcome not reported.
Adverse effects of antibiotics Follow‐up: 27 months	No adverse effects were reported in either group.		NR	26 (1 RCT)	⊕⊝⊝⊝ very lowa,b,c	No numerical data were reported.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; NA: not applicable; NR: not reported; P aeruginosa: Pseudomonas aeruginosa; RCT: randomised controlled trial.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aDowngraded once due to risk of bias; methodological information was limited and unclear in the included trial and there was a high risk of bias due to lack of blinding.
^bDowngraded once due to applicability: the included trial recruited only children; results are not applicable to adults.
^cDowngraded once due to imprecision: no numerical results available.

Summary of findings 9. 14 days inhaled AZLI plus 14 days placebo compared to 28 days inhaled AZLI.

Inhaled AZLI 14 days followed by placebo 14 days compared with AZLI 28 days for eradicating Pseudomonas aeruginosa in people with cystic fibrosis
Patient or population: children and adolescents with cystic fibrosis Settings: not stated Intervention: 14 days of AZLI followed by 14 days of placebo Comparison: 28 days of AZLI
Outcomes		Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		AZLI 28 days	AZLI 14 days plus placebo 14 days
Eradication of P aeruginosa from the respiratory tract: proportion of participants with a negative culture for PA during the 28 days following treatment Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months (28 days)	The proportion of participants with a negative culture was 63.4% (51.97).	The proportion of participants with a negative culture was 7.50% lower in the AZLI 14 group than the AZLI 28 group (24.80% lower to 9.80% higher).	NA	139 (1 RCT)	⊕⊝⊝⊝ very lowa,b,c
	Follow‐up: 6 to 24 months after onset of treatment	Outcome not reported at this time point
FEV1 % predicted		This outcome was not reported.
FVC % predicted		This outcome was not reported.
Growth and nutritional status		This outcome was not reported.
Frequency of infective pulmonary exacerbations		This outcome was not reported.
Isolation of other micro‐organisms from the respiratory tract		This outcome was not reported.
Adverse effects of antibiotics: number of participants reporting a serious adverse event		Outcome not reported at this time point.					Adverse events were reported at the 28‐day time point. There was no difference in serious adverse events between groups, RR 1.27 (95% CI 0.35 to 4.53)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AZLI: aztreonam lysine; CI: confidence interval; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; P aeruginosa: Pseudomonas aeruginosa; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aDowngraded once due to unclear risk of bias, particularly around randomisation and allocation concealment. The trial was described as randomised but no further details were given.
^bDowngraded once due to imprecision from a small number of participants.
^cDowngraded once due to indirectness as the trial was only conducted in children and adolescents. It is unclear whether the results would be reproducible in an adult population.

Summary of findings 10. Intravenous ceftazidime with tobramycin compared with oral ciprofloxacin.

Intravenous ceftazidime with tobramycin compared with oral ciprofloxacin for eradicating Pseudomonas aeruginosa in people with cystic fibrosis
Patient or population: adults and children with cystic fibrosis and a positive microbiological isolate of Pseudomonas aeruginosa from a respiratory tract specimen Settings: outpatients Intervention: IV ceftazidime with tobramycin Comparison: oral ciprofloxacin
Outcomes		Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		Oral ciprofloxacin	IV ceftazidime
Eradication of P aeruginosa from the respiratory tract: number of participants testing negative for P aeruginosa at 3 months and remaining free until 15 months Follow‐up: up to 6 months and 6 to 24 months after onset of treatment.	Follow‐up: up to 6 months	Outcome not reported at this time point					The primary outcome was the proportion of participants who were successfully eradicated at 3 months and remained free at 15 months.
	Follow‐up: 6 to 24 months after onset of treatment (15 months)	523 per 1000	439 per 1000 (340 to 570 per 1000)	RR 0.84 (0.65 to 1.09)	255 (1 RCT)	⊕⊕⊕⊕ higha	30 participants were excluded from the primary analysis as they did not have a sample taken at 5 months. Further sensitivity analyses confirmed the same results.
FEV1: mean FEV1 % predicted Follow‐up: 15 months		FEV1 % predicted was 84.11% after treatment with oral ciprofloxacin.	FEV1 % predicted in the IV ceftazidime group was 2.08 % higher (0.81% lower to 4.97% higher).	N/A	285 (1 RCT)	⊕⊕⊕⊕ higha
FVC: mean FVC % predicted Follow‐up: 15 months		FVC % predicted was 90.94% after treatment with oral ciprofloxacin.	FVC % predicted was 3.14% higher in the IV ceftazidime group (0.31% higher to 5.97% higher).	N/A	285 (1 RCT)	⊕⊕⊕⊕ higha
Growth and nutritional status: weight‐for‐age z score Follow‐up: 15 months		Weight‐for‐age z score was 0.13 in the oral ciprofloxacin group.	Weight‐for‐age z score was 0.02 lower in the IV ceftazidime group (0.15 lower to 0.11 higher).	N/A	285 (1 RCT)	⊕⊕⊕⊕ higha
Frequency of infective pulmonary exacerbations: number of participants experiencing an exacerbation Follow‐up: 15 months		356 per 1000	278 per 1000 (196 to 392 per 1000)	RR 0.78 (0.55 to 1.10)	285 (1 RCT)	⊕⊕⊕⊕ higha
Isolation of other micro‐organisms from the respiratory tract: number of participants isolating other micro‐organisms within the 15‐month follow‐up. Follow‐up: 15 months		There was no difference between treatments in the number of participants who grew other organisms: MRSA (RR 2.07, 95% CI 0.39 to 11.14); B cepacia (RR 0.51, 95% CI 0.10 to 2.76); Candida spp (RR 1.04, 95% CI 0.78 to 1.40); and Aspergillus spp (RR 0.72, 95% CI 0.38 to 1.37).			285 (1 RCT)	⊕⊕⊕⊕ higha
Adverse effects of antibiotics: Follow‐up: 15 months		There was no difference in serious adverse events (RR 0.97, 95% CI 0.43 to 2.16) or non‐serious adverse events (RR 0.97, 95% CI 0.75 to 1.24) between groups, except for URTI where there were fewer incidences in the oral antibiotic treatment group (RR 6.37, 95% CI 1.44 to 28.21).			285 (1 RCT)	⊕⊕⊕⊝ moderateb
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). B cepacia: Burkholderia cepacia; CI: confidence interval; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; IV: intravenous; MD: mean difference; MRSA: methicillin‐resistant Staphylococcus aureus; N/A: not applicable; NR: not reported; P aeruginosa: Pseudomonas aeruginosa; RCT: randomised controlled trial; RR: risk ratio; URTI: upper respiratory tract infection.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^aWe have not downgraded the evidence for this outcome despite the trial being open‐label. It is unlikely that knowledge of the allocation would influence the results for this outcome.
^bDowngraded once due to risk of bias; this was an open‐label trial, and it is unclear whether knowledge of treatment arm may have affected this outcome.

Background

Description of the condition

Cystic fibrosis (CF) is the most common life‐limiting, autosomal recessively inherited disease in populations of Northern European descent (Farrell 2018). Although this is a multisystem disease, the primary cause of death in CF is respiratory failure resulting from chronic pulmonary infection (FitzSimmons 1993). The most frequent cause of chronic pulmonary infection beyond infancy in people with CF is Pseudomonas aeruginosa and, once established, appears to be permanent in the majority of cases (Fitzsimmons 1996). A number of definitions have been used for chronic P aeruginosa infection in CF.

1. The presence of P aeruginosa in monthly specimens for six successive months or the development of precipitating antibodies to P aeruginosa, or both (Valerius 1991).

2. The culture of P aeruginosa from the sputum or respiratory secretions, on two or more occasions extending over six months or a shorter period if accompanied by a sustained rise of anti‐pseudomonal antibodies (UK CF Trust 2004).

3. The isolation of P aeruginosa in more than 50% of months over a 12‐month period (Lee 2003) ‐ the second and subsequent positive specimens in the same month do not count. Conversely, eradication is defined as all monthly specimens negative for P aeruginosa over 12 months.

4. Three or more isolates of P aeruginosa in a 12‐month period (UK CF Registry 2012).

We have used the first definition in this systematic review.

The age‐specific prevalence of P aeruginosa in preschool children is under 5% (UK CF Trust 2021). Some authors have suggested that the use of prophylactic anti‐staphylococcal antibiotic therapy in early childhood may predispose to chronic P aeruginosa infection (Ratjen 2001b; Stutman 2002). However, this effect was not seen in a systematic review of prophylactic anti‐staphylococcal antibiotic use including over 400 participants (Rosenfeld 2020).

In children who are too young to expectorate, cough swabs or oropharyngeal swabs are the only respiratory specimens which can be easily obtained. These do not reliably predict the presence of P aeruginosa in the lower respiratory tract (Armstrong 1996; Rosenfeld 1999), whereas flexible fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) may detect positive P aeruginosa in children with negative cough swabs or oropharyngeal swabs (Douglas 2009; Hilliard 2007). Sputum cultures have been shown to accurately reflect lower respiratory tract organisms in expectorating children and adults (Iacocca 1963; Thomassen 1984). Around a third of people with CF have chronic infection with P aeruginosa by their mid‐20s (UK CF Trust 2021), although prior to chronic infection P aeruginosa is often isolated intermittently from respiratory tract specimens. This may represent transient colonies of P aeruginosa within the lower respiratory tract, or alternatively it may reflect the difficulties in accurately detecting P aeruginosa in the lungs of young people with CF (Burns 2001). The quantity and type of P aeruginosa present in the lower respiratory tract changes as infection becomes established. It is known that P aeruginosa has two major phenotypes ‐ mucoid and non‐mucoid. Following first isolation there is a progressive increase in the density of P aeruginosa colonies in the lower respiratory tract (Rosenfeld 2001). Initial isolates often show a non‐mucoid phenotype; however, as infection progresses a mucoid phenotype may prevail and will be more difficult to eradicate. Douglas has reported a relatively high prevalence (18.2%) of mucoid P aeruginosa at first isolation in infants diagnosed with CF during newborn screening, speculating that the notion of transformation from non‐mucoid to mucoid phenotype under environmental pressure may be inaccurate in young children (Douglas 2009). It has been reported that P aeruginosa provokes an inflammatory response of the lower respiratory tract (Muhlebach 1999), and there is a marked step‐up in this inflammatory response as the number of P aeruginosa colonies increases (Armstrong 1996).

The presence of P aeruginosa in respiratory secretions is a major predictor of mortality in children with CF (Emerson 2002). Individuals with CF infected with P aeruginosa also suffer greater morbidity with a more rapid deterioration in lung function (Emerson 2002; Pamukcu 1995), and a more rapid decline in chest radiograph score (Kosorok 2001), poor growth, reduced quality of life (QoL), increased hospitalisation and increased need for antibiotic treatment (Ballman 1998; Nixon 2001; Winnie 1991). Some studies suggest there is a temporal relationship between the onset of chronic infection and increased morbidity (Abman 1991; Hudson 1993; Kosorok 2001; Parad 1999), whilst others do not support these findings (Kerem 1990; Rosenfeld 2001). On balance, there seems to be good evidence from well‐designed non‐experimental studies that clinical state deteriorates after first isolation of P aeruginosa.

There is evidence that, when P aeruginosa is cleared from respiratory secretions, it is not simply suppressed because, when infection recurs, this is with a genetically distinct organism in most cases (Munck 2001). However, a recent study from a Danish‐based group found that by using omics‐based tracking in nearly half (43%) of those treated, recurrence was due to the same clone type, even after a period of negative cultures for more than six months. This suggests that P aeruginosa persistence and suppression may be more common despite apparent eradication (Bartell 2021).

Description of the intervention

Several strategies exist to treat early infection with P aeruginosa, and include the use of the inhaled antibiotics such as colistin and tobramycin (Littlewood 1985; Ratjen 2001a), oral quinolones such as ciprofloxacin (Taccetti 2005), and intravenous (IV) antibiotics usually consisting of combination of an aminoglycoside with a beta‐lactam (Döring 2000; Douglas 2009).

As well as antibiotic treatment of P aeruginosa given at the time of first isolation, other strategies have the potential to prevent or delay infection of the respiratory tract. These include avoidance of contact with people who carry P aeruginosa (UK CF Trust 2004), and the development of vaccines against P aeruginosa (Johansen 2015). Most CF centres advocate frequent microbiological surveillance with attempts to eradicate P aeruginosa when it first appears in the lung (Döring 2000).

How the intervention might work

Uncontrolled series have indicated that a variety of anti‐pseudomonal antibiotics either singly (Littlewood 1985; Ratjen 2001a), or in combination (Vazquez 1993), at first isolation may delay the onset of chronic infection. A trial using historical controls suggested that oral ciprofloxacin and nebulised colistin are effective in delaying or preventing chronic infection (Frederiksen 1997). An uncontrolled pilot study of IV therapy suggested that IV treatment alone was less effective in delaying the onset of chronic infection (Steinkamp 1989). There is also evidence supporting eradication therapy from long‐term observational studies of chronic infection with P aeruginosa in CF clinics, such as the study reported by Lee 2004.

Why it is important to do this review

There are multiple different eradication regimens that have been described using different anti‐pseudomonal antibiotics in different combinations of IV, oral or nebulised (or both), and with varying doses and duration of therapy (Lee 2009). Additionally, given the expense of chronic anti‐pseudomonal suppressive therapy, there is a clear rationale for early eradication from a cost‐effectiveness perspective and this is supported by observational data (Taccetti 2005); however, there has not been any formal evaluation of cost‐effectiveness to date.

This is an update of a Cochrane Review first published in 2003, and regularly updated since (Wood 2003; Wood 2006; Langton‐Hewer 2009; Langton‐Hewer 2014; Langton‐Hewer 2017).

Objectives

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.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) were eligible for inclusion in this review.

Types of participants

We included people with CF of all ages and disease severity, diagnosed clinically and by sweat or genetic testing (or both), with a first ever positive microbiological isolate of P aeruginosa from a respiratory tract specimen. We also included trials where the participants had been proven to be free of P aeruginosa for at least six months before a new isolation and should not have currently been receiving Pseudomonas‐suppressing treatment (such as daily inhaled antibiotic therapy). Participants should have been enrolled into a trial within six months (post hoc change ‐ previously not more than two months) from isolation of P aeruginosa. In a further post hoc change, we also altered our eligibility criteria to allow trials where all participants received some eradication therapy before randomisation (see Differences between protocol and review).

Types of interventions

We included combinations of inhaled, oral or IV antibiotics with the aim of eradicating first pulmonary isolates of P aeruginosa compared with placebo or usual treatment (or both), or other combinations of inhaled, oral or IV antibiotics.

Note on terminology: the following synonyms and acronyms are used for inhaled tobramycin in the literature: tobramycin solution for inhalation (TSI); tobramycin inhalation solution (TIS); and tobramycin nebuliser solution (TNS). We will use the term TNS in this manuscript for consistency (except where other terminology is included in the title of an included trial, or when we quote directly from the trial).

Types of outcome measures

We planned to assess the following outcome measures.

Primary outcomes

1. Eradication of P aeruginosa from the respiratory tract as defined by

   1. clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures at 1, 2, 3, 6, 12 and 24 months after commencement of therapy

   2. time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures

Secondary outcomes

1. Mortality

2. QoL assessment measured using standardised and validated QoL scores (e.g. Cystic Fibrosis Questionnaire ‐ Revised (CFQ‐R) (Quittner 2009))

3. Spirometric lung function (% predicted values for age, sex and height)

   1. forced expiratory volume in one second (FEV₁)

   2. forced vital capacity (FVC)

   3. forced expiratory flow between 25% and 75% of vital capacity (FEF_25-75)

4. Growth and nutritional status as measured by

   1. weight (kg)

   2. height (children) (cm)

   3. body mass index (BMI) or z score

5. Frequency of respiratory exacerbations as defined by

   1. frequency of infective pulmonary exacerbations expressed as the number of exacerbations per patient year

   2. time to next course of IV antibiotics from commencement of therapy

   3. days in hospital expressed as days in hospital per patient year

   4. days of antibiotic usage expressed as days of antibiotic usage per patient year

6. Isolation of other micro‐organisms from the respiratory tract (e.g. Staphylococcus aureus, non‐tuberculous mycobacteria (NTM)) expressed as the number of positive cultures per patient year (where available, we planned to describe the microbiology detection method in view of the differences in sensitivity and specificity of oropharyngeal, sputum and BAL samples for bacteriology and mycology)

7. Adverse effects of antibiotics, e.g. renal or auditory impairment and hypersensitivity reactions

Additional outcomes which have arisen during the review

1. Time to chronic infection (as defined above in Description of the condition)

2. Clinical and radiological scores

3. Cost‐effectiveness (we planned to compare trials looking at cost‐effectiveness, where possible)

Search methods for identification of studies

We searched for all relevant published and unpublished trials without restrictions on language, year or publication status.

Electronic searches

Relevant trials were identified from the Group's Cystic Fibrosis Trials Register using the terms: antibiotics AND (pseudomonas aeruginosa OR mixed infections) AND (eradication OR unknown).

The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library), weekly searches of MEDLINE, a search of Embase to 1995 and the prospective handsearching of two journals ‐ Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work has been identified by searching the abstract books of three major CF conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the Trials Register, please see the relevant sections of the Group's website.

Date of the most recent search of the Group's trials register: 24 March 2022.

We also searched the following trial registries.

1. US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 6 April 2022).

2. World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (trialsearch.who.int/; searched 6 April 2022).

3. International Standard Randomised Controlled Trial Number (ISRCTN) Registry (www.isrctn.com/; searched 6 April 2022).

For details of our search strategies, please see Appendix 1.

Searching other resources

We checked the reference lists of included trials and any systematic reviews identified from the searches for any relevant trials we may have missed.

Data collection and analysis

Selection of studies

For the original review, two authors (DW, AS) independently selected the trials to be included in the review. From Issue 3, 2009 of the Cochrane Library, two authors (SLH, AS) selected the trials to be included in the review. For the current 2023 update, three authors (SS, NR, AY) screened and selected trials. Where there was disagreement on the suitability of a trial for inclusion in the review, we reached a consensus by discussion.

Data extraction and management

For the original review, two authors (DW, AS) extracted data; from 2009 to 2017 this was undertaken by SLH and AS. For the 2023 update, three different authors (SS, NR, AY) undertook data extraction since the original review authors are authors on one of the newly included trials (TORPEDO 2020). Each author independently extracted data using standard data acquisition forms. Where there was disagreement on the data extracted, we reached a consensus by discussion.

We planned to group outcome data into those measured at up to one month, greater than one month to three months, greater than three months to six months and greater than six months to 12 months, then annually thereafter. In addition, we previously stated that if trials recorded outcome data at other time periods, we would also consider examining these data. Some trials reported data at two months for some outcomes, and we have included these data within the review. The Taccetti 2012 trial reported cumulative data at six months and final follow‐up data at a median of 16 months (range 12 to 28 months); we have included both time points in our analysis. The Treggiari 2011 trial presented cumulative data for pulmonary exacerbations and isolates of P aeruginosa for the 70‐week follow‐up period, and we have reported and analysed these data in this review.

Assessment of risk of bias in included studies

For earlier versions of this review, in order to assess the risk of bias, each author independently assessed the methodological quality of each trial, based on the method described by Schulz 1995. For the current update, each author independently assessed the risk of bias using the tool recommended by Cochrane (Higgins 2017). We judged the risks of bias as high, unclear or low for the domains of:

1. sequence generation;

2. allocation concealment;

3. blinding (risk of bias increased as the level of blinding decreased);

4. incomplete outcome data (the risk of bias increased if any withdrawals were not adequately described and reasons for withdrawals given, or if the withdrawals were not equal across groups);

5. selective outcome reporting (bias increased if stated outcome measures were only partially reported or not reported at all);

6. other potential sources of bias.

Where there was disagreement on the quality and risk of bias of a trial, we reached a consensus by discussion.

Measures of treatment effect

For binary outcome measures (eradication of P aeruginosa, mortality, isolation of micro‐organisms and adverse effects), in order to allow an intention‐to‐treat analysis, the authors sought data on the number of participants with each outcome event, by allocated treatment group, irrespective of compliance and whether the participant was later thought to be ineligible or otherwise excluded from treatment or follow‐up. We calculated a pooled estimate of the treatment effect for each outcome across trials ‐ the odds ratio (OR) or the ratio of the odds of an outcome among treatment allocated participants to the corresponding odds among controls, with 95% confidence intervals (CIs). We presented binary data on clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures and occurrence of chronic infection with P aeruginosa at multiple time points. We calculated the OR at each time point separately, thus ignoring the correlation between time points.

For continuous outcomes (QoL, lung function, weight, height, BMI, number of respiratory exacerbations, days in hospital, days of antibiotic use, clinical and radiological scores), in order to allow an intention‐to‐treat analysis, we sought outcome data by allocated treated group, irrespective of compliance and whether the participant was later thought to be ineligible or otherwise excluded from treatment or follow‐up. We recorded either mean change from baseline for each group or mean post‐treatment or intervention values and standard deviation (SD). We calculated a pooled estimate of treatment effect by calculating the mean difference (MD) with 95% CIs.

In this version of the review, we entered time‐to‐event data into the meta‐analysis using the log hazard ratio. This was possible for the outcome 'time to pulmonary exacerbation' (severe or any), in the comparison of cycled versus culture‐based therapy (Analysis 3.5; Analysis 3.7) and ciprofloxacin versus placebo (Analysis 4.5; Analysis 4.7). We used the generic inverse variance (GIV) to analyse the data for time to next isolation of P aeruginosa from the Ratjen 2010 trial. For future updates of this review, for time‐to‐event data, such as time to next P aeruginosa infection or time to chronic infection, we will attempt to obtain individual participant data (IPD). We will use the IPD to provide estimates of the log hazard ratio and its standard error (SE), and plan to combine time‐to‐event data from trials in a meta‐analysis.

3.5. Analysis.

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 5: Time to severe pulmonary exacerbation

3.7. Analysis.

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 7: Time to pulmonary exacerbation (any severity)

4.5. Analysis.

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 5: Time to severe pulmonary exacerbation

4.7. Analysis.

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 7: Time to pulmonary exacerbation (any severity)

We have reported longitudinal data as individual time points. We realise that this method ignores any correlation between the participants; however, we have been unable to analyse these data using more appropriate methods as we do not have the correlation coefficient for these data. If in the future, we are able to obtain the correlation coefficient, we will analyse these data more appropriately.

Where trials included a health economic component, we have reported results directly from the trial paper. If more data are available in a future update, we will conduct a full or partial economic evaluation of interventions to eradicate P aeruginosa.

Unit of analysis issues

Cross‐over trials were not eligible for inclusion in this review.

The natural history of infection with P aeruginosa in CF comprises an initial infection with the organism, usually in planktonic form, followed by chronic infection (in which the P aeruginosa frequently exists in the mucoid state). In the planktonic form, antibiotics can eradicate the organism; however, persistent infection is associated with biofilm growth and adaptive evolution mediated by genetic variation. The development of mucoidy, hypermutability and the acquisition of mutational antibiotic resistance are important factors associated with persistent infection and are associated with increased difficulty in eradication (Ciofu 2012).

If active treatment was compared to a placebo in a cross‐over trial, given the progression of infections due to of P aeruginosa, the group receiving the active treatment after placebo would be at a disadvantage compared with those receiving active treatment first. During placebo treatment, P aeruginosa may form a biofilm, so it would not be able to be eradicated during the active treatment phase. Hence, a cross‐over trial is an inappropriate design, and we have not included cross‐over trials in this review.

Dealing with missing data

In trials where outcome data were unavailable for randomised participants, we performed an available‐case analysis. This available‐case analysis included data on only those participants whose results are known, using as a denominator the total number of people who completed the trial for the particular outcome in question.

When data were incomplete, we imputed the missing data to provide best‐case and worst‐case scenarios, in order to show the range of possible results for the combined analysis (Analysis 1.4; Analysis 1.5). The best‐case scenario analysis is based on the assumption that all the missing data points represented beneficial clinical outcomes, whereas the worst‐case analysis assumes that all missing data points had a negative clinical outcome.

1.4. Analysis.

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 4: Positive respiratory culture for P aeruginosa (combined) ‐ best case

1.5. Analysis.

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 5: Positive respiratory culture for P aeruginosa (combined) ‐ worst case

Assessment of heterogeneity

For future updates of this review, if we are able to combine data from different trials, we will test for heterogeneity using the I² statistic (Deeks 2022). We will consider values of I² indicative of levels of heterogeneity as follows.

1. 0% to 40%: might not be important

2. 30% to 60%: may represent moderate heterogeneity

3. 50% to 90%: may represent substantial heterogeneity

4. 75% to 100%: considerable heterogeneity

We accept that the importance of the observed value of I² depends firstly on the magnitude and direction of effects and secondly on strength of evidence for heterogeneity (e.g. P value from the Chi² test, or a CI for I²). In a future version of this review (with more trials included in the meta‐analysis of individual treatment comparisons), if we find evidence of at least substantial clinical heterogeneity (as defined above) in the included trials, we will perform a random‐effects analysis.

Assessment of reporting biases

We sought evidence of reporting bias by comparison of the reported outcomes with those listed in the trial's methodological description. Where important outcomes have not been identified, we have requested the original trial protocol from the authors.

Data synthesis

We have analysed the data using a fixed‐effect model. In future updates of this review, if we find evidence of at least substantial clinical heterogeneity (as defined above) in the included trials, we plan to perform a random‐effects analysis.

Subgroup analysis and investigation of heterogeneity

If we identify a moderate degree of heterogeneity or higher in a future update (Deeks 2022), and are able to combine a sufficient number of trials (at least 10), then we will investigate this with subgroup analyses. We plan to categorise participants, if possible, as P aeruginosa‐free and P aeruginosa‐naive according to the definition by Lee 2003. We will analyse these subgroups separately.

Sensitivity analysis

We also planned to test the robustness of our results with the following sensitivity analyses:

1. trials where participants receive treatment within three months of isolation of P aeruginosa versus those where the interval is between three and 12 months; to do this we would need to include studies where eradication treatment was started up to 12 months after initial isolation of P aeruginosa;

2. trials with high risk of bias versus low risk of bias for generation of allocation sequence;

3. trials with a high risk of bias versus a low risk of bias for concealment of allocation;

4. multicentre versus single‐centre trials.

We were not able to carry out sensitivity analyses as there were not enough trials to combine in a meta‐analysis.

Summary of findings and assessment of the certainty of the evidence

In a post hoc change in line with current Cochrane guidance, at the 2023 update, we added a summary of findings table for each comparison presented in the review. We selected the following seven outcomes to report (chosen based on relevance to clinicians and consumers):

1. eradication of P aeruginosa from the respiratory tract;

2. FEV₁ (% predicted);

3. FVC (% predicted);

4. weight (kg);

5. frequency of infective pulmonary exacerbations;

6. isolation of other micro‐organisms from the respiratory tract; and

7. adverse effects of antibiotics, e.g. renal or auditory impairment and hypersensitivity reactions.

For eradication of P aeruginosa from the respiratory tract, we reported data at 'up to six months' and also 'six months up to 24 months' from treatment onset.

For all other outcomes we reported at 'six months up to 24 months' from treatment onset. One trial reported spirometry at 27 months, and we have included these data in the summary of findings tables for reference (Ratjen 2010).

We determined the certainty of the evidence using the GRADE approach; and downgraded evidence in the presence of a high risk of bias in at least one domain, indirectness of the evidence, unexplained heterogeneity or inconsistency, imprecision of results, high probability of publication bias. We downgraded evidence by one level if they considered the limitation to be serious and by two levels if very serious.

Results

Description of studies

Please see the characteristics tables for further information (Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies). We present the flow of references through assessment stages in Figure 1.

1.

Study flow diagram.

Results of the search

Our search identified a total of 70 trials; none of these were cross‐over trials; although one trial did offer an option for participants to cross over to the alternative treatment arm after the initial 28‐day parallel trial (EARLY 2019). Of these 70 trials, 11 met our inclusion criteria (ALPINE2 2017; EARLY 2019; Gibson 2003; OPTIMIZE 2018; Proesmans 2013; Ratjen 2010; Taccetti 2012; TORPEDO 2020; Treggiari 2011; Valerius 1991; Wiesemann 1998). We had previously listed three of these trials in the review as ongoing, but as these have now been completed we have included them; two have been published as full papers (EARLY 2019; TORPEDO 2020), and the third has results posted on the trial registration website (ALPINE2 2017). Three trials are still ongoing, and we will include data from these trials in a future update of this review, once the results have been published (EUCTR2007‐003868‐22‐FR; EUCTR2011‐006171‐19‐IT; EUCTR2015‐003881‐96‐IT). We excluded 55 trials (see below), and one trial is listed under Studies awaiting classification (Noah 2010). We have contacted the investigators of this trial for further information to allow us to include or exclude it at a future update.

Included studies

The 11 included trials enrolled a total of 1449 participants (ALPINE2 2017; EARLY 2019; Gibson 2003; OPTIMIZE 2018; Proesmans 2013; Ratjen 2010; Taccetti 2012; TORPEDO 2020; Treggiari 2011; Valerius 1991; Wiesemann 1998).

Trial characteristics

All 11 included trials were randomised controlled trials (RCTs) of parallel design. One trial reported stratification for age and participating centre (Gibson 2003), another trial reported stratification by age and FEV₁ values as an expression of illness severity (Taccetti 2012); one trial stratified by age (OPTIMIZE 2018); one trial stratified by participating centre (TORPEDO 2020); the remaining seven trials did not use stratification (ALPINE2 2017; EARLY 2019; Proesmans 2013; Ratjen 2010; Treggiari 2011; Valerius 1991; Wiesemann 1998). In one trial the first treatment phase was a double‐blind parallel trial, which was followed by an optional phase where participants could choose to switch to the alternative treatment arm; we have only included the initial parallel phase in our review (EARLY 2019). Five trials stated that they were double‐blind (ALPINE2 2017; EARLY 2019; Gibson 2003; OPTIMIZE 2018; Wiesemann 1998); the Treggiari 2011 trial used placebo to blind for ciprofloxacin, but not for TNS (described in the paper as TSI); the other trials could not be blinded due to differing treatment regimens (Proesmans 2013; Ratjen 2010; Taccetti 2012; TORPEDO 2020; Valerius 1991).

Nine trials were multicentre (ALPINE2 2017; EARLY 2019; Gibson 2003; OPTIMIZE 2018; Ratjen 2010; Taccetti 2012; TORPEDO 2020; Treggiari 2011; Wiesemann 1998), and the remaining two were single‐centre trials (Proesmans 2013; Valerius 1991). Six trials were based in Europe (Proesmans 2013; Ratjen 2010; Taccetti 2012; TORPEDO 2020; Valerius 1991; Wiesemann 1998), and three took place in North America (Gibson 2003; OPTIMIZE 2018; Treggiari 2011). One trial was carried out in Europe, Israel and North America (ALPINE2 2017), and the EARLY 2019 trial was carried out across nine countries in Europe, North America, North Africa and Russia.

The duration of the trials varied and ranged from 28 days (EARLY 2019; Gibson 2003) to 27 months (Valerius 1991). The duration of the intervention varied greatly, from three weeks (Valerius 1991) to 18 months (OPTIMIZE 2018).

Participants

The number of participants in each trial ranged from 21 to 304 and were as follows: 304 in Treggiari 2011; 286 in TORPEDO 2020; 223 in Taccetti 2012; 221 in OPTIMIZE 2018; 149 in ALPINE2 2017; 88 in Ratjen 2010; 58 in Proesmans 2013; 51 in EARLY 2019; 26 in Valerius 1991; 22 in Wiesemann 1998; and 21 in Gibson 2003. The Gibson trial reported that the planned sample size was 98 participants, but randomisation was stopped after an early interim analysis by the Data Monitoring Committee was undertaken due to poor accrual. This analysis showed a statistically significant treatment effect and so the trial was stopped (Gibson 2003).

Only three trials recruited adult participants; Taccetti 2012 recruited participants aged from one to 35 years, and the Ratjen 2010 trial included participants over six months of age. The TORPEDO trial included adults and children, but only 15 of the 286 participants were over 18 years (TORPEDO 2020). Two trials were restricted to younger children: three months to six years (EARLY 2019; Gibson 2003); one to children aged two to nine years (Valerius 1991); and one to 12 years (Treggiari 2011); the final four trials included children between the ages of one month and 18 years (ALPINE2 2017; OPTIMIZE 2018; Proesmans 2013; Wiesemann 1998).

All 11 trials had approximately equal numbers of males and females.

All 11 trials specified that participants had to have microbiological evidence of recent onset of airway infection with P aeruginosa. However, the interval allowed between isolation of P aeruginosa and randomisation to treatment varied greatly, from three weeks (TORPEDO 2020) to as long as six months (Treggiari 2011). Two trials additionally specified that individuals with raised titres to anti‐pseudomonal antibodies were excluded from the trial (Ratjen 2010; Wiesemann 1998). Other data from the EPIC trial (Treggiari 2011) have shown that raised antibodies to P aeruginosa (anti‐alkaline protease and anti‐exotoxin A) are associated with an increased risk of recurrence in the 60 weeks following eradication treatment (Anstead 2013). Trials excluding participants with raised antibodies might therefore be expected to achieve higher eradication rates.

Intervention

Trials used various combinations of intravenous ceftazidime and tobramycin, inhaled tobramycin, azithromycin, inhaled colistin, oral ciprofloxacin, inhaled aztreonam, placebo and no treatment. Four trials were placebo‐controlled (EARLY 2019; Gibson 2003; OPTIMIZE 2018; Wiesemann 1998); one trial compared 14 days of treatment versus 28 days of the same treatment (ALPINE2 2017); one trial compared active treatment to no treatment (Valerius 1991); and four open‐label trials compared different active treatments (Proesmans 2013; Ratjen 2010; Taccetti 2012; TORPEDO 2020). The design of the EPIC trial was complex, with randomisation to cycled treatment with TNS or culture‐based treatment and further randomisation to additional oral ciprofloxacin or placebo (Treggiari 2011).

Three trials compared tobramycin to placebo (EARLY 2019; Gibson 2003; Wiesemann 1998). Two trials used TNS (known as TOBI^® and now marketed by Novartis) at a dose of 300 mg twice‐daily for 28 days (EARLY 2019; Gibson 2003); the third trial used aerosolised tobramycin parenteral preparation (Eli Lilly, Bad Homburg, Germany) at a dose of 80 mg twice‐daily for 12 months (Wiesemann 1998).

Ratjen 2010 also used TNS and evaluated a short (28 days) versus a longer (56 days) course of treatment.

Participants in the Treggiari 2011 trial were randomised to one of four arms; they received either cycles of four weeks of treatment with nebulised TNS (with or without ciprofloxacin) in every 12‐week period or TNS (with or without ciprofloxacin) only when respiratory culture was positive for P aeruginosa. All trial participants had an initial 28‐day course of TNS, with an additional 28 days given if the participant remained positive after initial treatment. Ciprofloxacin or placebo was not given with the second course of TNS, and follow‐up was for 18 months from randomisation and first treatment with TNS (Treggiari 2011).

One trial compared 14 days of inhaled aztreonam lysine (AZLI) followed by 14 days of an inhaled placebo with 28 days of AZLI (ALPINE2 2017).

One trial compared the addition of oral azithromycin to inhaled tobramycin with an oral placebo in addition to inhaled tobramycin (OPTIMIZE 2018).

Three trials evaluated oral ciprofloxacin in combination with inhaled colistin (Proesmans 2013; Taccetti 2012; Valerius 1991). Proesmans 2013 compared oral ciprofloxacin 30 mg/kg/day in combination with colistin 2 million units (MU) twice daily for three months to TNS 300 mg twice daily for 28 days. In the Taccetti 2012 trial, both arms received oral ciprofloxacin 30 mg/kg/day for 28 days, additionally one group received 28 days of inhaled colistin while the second group received 28 days TNS. Valerius 1991 compared ciprofloxacin 250 mg plus colistin 1 MU to ciprofloxacin 750 mg plus colistin 1 MU, both given twice daily for three weeks for initial and any subsequent isolate of P aeruginosa, to no treatment.

The TORPEDO trial compared 10 days of IV ceftazidime and tobramycin with three months of oral ciprofloxacin (TORPEDO 2020), both groups also receiving three months of inhaled colistin.

Outcome measures

The most widely used primary outcome measure was eradication of P aeruginosa from respiratory secretions, though definitions of eradication differ considerably between trials. In the Gibson 2003 trial, the primary outcome was the change in P aeruginosa density in BAL from baseline to 28 days. However, the trial also looked at eradication at 28 days, and defined eradication as a density of P aeruginosa in BAL of less than 20 colony forming units (CFU). The EARLY 2019 trial reported negative respiratory culture at 28 days. Proesmans 2013 defined eradication as a negative culture result for P aeruginosa (from sputum, cough swab or BAL) at 28 days or three months (depending on which intervention the participant received). Both trials based successful eradication on a single specimen (Gibson 2003; Proesmans 2013). In contrast, Taccetti 2012 used a more stringent definition of eradication as per guidance published by the UK CF Trust of three negative cultures in a six‐month period (UK CF Trust 2004). Ratjen 2010 used the median time to recurrence of any strain of P aeruginosa during a 27‐month follow‐up period. In the oldest trial, the primary outcome measure was time to chronic infection with P aeruginosa, defined as the presence of P aeruginosa in monthly sputum samples for six consecutive months or the development of precipitating serum antibodies against P aeruginosa or both (see Description of the condition for other definitions of chronic infection) (Valerius 1991). There were two primary outcomes in the Treggiari 2011 trial, time to pulmonary exacerbation requiring IV antibiotics and proportion of P aeruginosa positive cultures over the 18‐month trial period. The TORPEDO 2020 trial looked at eradication from respiratory samples at three months from commencing treatment and also at remaining free of infection at 15 months.

The primary outcome in the OPTIMIZE 2018 trial was time to a protocol‐defined exacerbation, but investigators reported the number of participants with negative respiratory culture for P aeruginosa after the first quarter of therapy. One of the secondary outcomes was time to P aeruginosa recurrence after the first treatment period (OPTIMIZE 2018). Similarly, a second trial reported on the percentage of participants with negative cultures over the 28 days of treatment and then reported time to recurrence over a 108‐week follow‐up period (ALPINE2 2017).

Other measured outcomes included less severe pulmonary exacerbations, Pseudomonas antibody levels, lung function, nutritional status, modified Shwachman score and monitoring for adverse clinical and microbiological effects.

Excluded studies

We excluded 55 trials from our analysis for a number of reasons. Three trials were not randomised (Gibson 2007; Postnikov 2000; Schelstraete 2010) and one trial was an observational study (Ballman 1998). Four trials did not have a control group (Heinzl 2002; Littlewood 1985; Ratjen 2001a; Steinkamp 1989), and a further five used a historical control group (Frederiksen 1997; Griese 2002; Kenny 2009; Taccetti 2005; Vazquez 1993). A total of 25 trials involved participants with chronic P aeruginosa infection (Bustamante 2014; Clancy 2013; Coates 2011; Elborn 2015; Flume 2015a; Flume 2015b; Flume 2016; Geller 2011; Goss 2009; Konstan 2010; Konstan 2011; Konstan 2015; Latzin 2008; Lenoir 2007; Mazurek 2012; Oermann 2009; Postnikov 2007; Prayle 2013; Ramsey 1999; Retsch‐Bogart 2008; Retsch‐Bogart 2009; Steinkamp 2007; Stockmann 2015; Trapnell 2012; Wainwright 2011b). Two trials were designed to evaluate a diagnostic technique for P aeruginosa (Brett 1992; Wainwright 2011a). A further five trials evaluated symptomatic rather than eradication treatment (Church 1997; Frost 2021; Hansen 2015; Herrmann 2017; Schaad 1997), and one was of a prophylactic antibiotic regimen to prevent infection with P aeruginosa (Tramper‐Stranders 2009). Seven trials looked at pharmacokinetics and drug tolerability (Alothman 2002; Alothman 2005; Geller 2007; Rietschel 2009; Ruddy 2013; Schuster 2013; Stass 2013), and the final two trials looked at antibiotic sinonasal nebulisation aiming to eradicate from the sinuses only (Di Cicco 2014; Mainz 2014).

Studies awaiting assessment

One single‐centre, randomised, prospective trial is currently awaiting assessment (Noah 2010). The trial enrolled children with CF (stable disease) and positive surveillance cultures for P aeruginosa. Investigators compared twice‐daily nebulised tobramycin (300 mg) for four weeks or intravenous ceftazidime with tobramycin for two weeks at standard weight‐adjusted doses. The primary efficacy endpoint was change in BAL fluid percentage neutrophils from the most affected lobe at bronchoscopy. Secondary outcomes included change in BAL fluid differential cell counts, cytokines and bacterial quantity.

Eight out of 15 participants had a first ever isolate of P aeruginosa and their data are eligible to be included in this review; however, these outcome data are not published separately, and we have contacted the lead author for them.

Ongoing studies

Three trials are listed as ongoing (EUCTR2007‐003868‐22‐FR; EUCTR2011‐006171‐19‐IT; EUCTR2015‐003881‐96‐IT).

The three ongoing trials are only available as trial registration documents; all three trials include children and adults with CF and new identification of P aeruginosa infection, with the objective of eradicating P aeruginosa (EUCTR2007‐003868‐22‐FR; EUCTR2011‐006171‐19‐IT; EUCTR2015‐003881‐96‐IT).

One trial compares inhaled tobramycin to placebo (EUCTR2007‐003868‐22‐FR); a second trial compares two different antibiotic protocols (oral ciprofloxacin and inhaled promixin versus oral ciprofloxacin and inhaled tobramycin (EUCTR2011‐006171‐19‐IT); and the third trial compares inhaled aztreonam for 14 days versus inhaled aztreonam for 29 days (EUCTR2015‐003881‐96‐IT).

The primary outcome in all three trials is eradication, with secondary outcomes including safety, time to recurrence, lung function, growth indices, number of exacerbations and antibiotic use (EUCTR2007‐003868‐22‐FR; EUCTR2011‐006171‐19‐IT; EUCTR2015‐003881‐96‐IT).

Risk of bias in included studies

Please see further information in the risk of bias sections of the tables (Characteristics of included studies) and the graphical risk of bias summary (Figure 2).

2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Generation of allocation sequence

All 11 trials were described as RCTs; six trials did not state the method of sequence generation, hence we judged these trials to have an unclear risk of bias (ALPINE2 2017; EARLY 2019; Gibson 2003; Proesmans 2013; Ratjen 2010; Valerius 1991). We judged the remaining five trials to have a low risk of bias (OPTIMIZE 2018; Taccetti 2012; TORPEDO 2020; Treggiari 2011; Wiesemann 1998). One trial used an adaptive randomisation (dynamic allocation based on minimisation) method to ensure equal representation in each study arm for each age strata (OPTIMIZE 2018). In a second trial, investigators describe a balanced randomisation sequence that was created using statistical software using permuted blocks of size 10 (Taccetti 2012). The TORPEDO 2020 trial employed a secure web‐based randomisation system, which was controlled centrally, and randomisation lists were generated by a statistician who had no involvement in the trial. Treggiari 2011 employed a computerised random number generator to assign treatments within permuted blocks of 12. In the Wiesemann 1998 trial, the allocation sequence was generated using a coin flip; there is no information as to who was responsible for the coin flip or what controls were in place to ensure validity of the result of the coin flip; however we have still judged this to have a low risk of bias.

Allocation concealment

Seven trials did not report how allocation was concealed, and we judged these to have an unclear risk of bias (ALPINE2 2017; EARLY 2019; Gibson 2003; Proesmans 2013; Ratjen 2010; Valerius 1991; Wiesemann 1998). We deemed the remaining four trials to have adequate allocation concealment and rated them to be at low risk of bias for this domain (OPTIMIZE 2018; Taccetti 2012; TORPEDO 2020; Treggiari 2011). In the Taccetti 2012 trial, the staff involved in randomisation and in treatment assignments were "kept separate". In the Treggiari 2011 trial, randomisation was remote and so allocation was concealed.

Blinding

Five trials were reported as double‐blind RCTs, and we graded these as having a low risk of performance and detection bias (ALPINE2 2017; EARLY 2019; Gibson 2003; OPTIMIZE 2018; Wiesemann 1998). The protocol for ALPINE2 2017 stated that the participants and the investigators were blinded. Gibson 2003 did not provide any details in the published paper regarding who was blinded or the method of blinding. However, in response to a request for further information, Dr Gibson confirmed that drugs and placebo were sufficiently masked that neither participants nor clinicians were able to differentiate between them (Gibson 2003). The OPTIMIZE 2018 trial reported that treatment arms were unknown to participants, parents, and site research staff, and we graded this as low risk of bias. Wiesemann 1998 reported that participants were blinded as the placebo inhalation had a similar taste to the treatment inhalation; while it is not clear whether the clinicians administering the treatment were blinded to treatment allocation, we still judged this trial to have a low risk of bias.

We judged two trials to have an unclear risk of bias (TORPEDO 2020; Treggiari 2011). The TORPEDO 2020 trial was open‐label and whilst objective outcomes (eradication of P aeruginosa) are unlikely to have been at risk of bias through lack of blinding, this may not be the case for subjective outcomes such as QoL and treatment burden. In the Treggiari 2011 trial, the oral ciprofloxacin treatment was blinded, but the TSI was open‐label.

We judged the remaining four trials to have a high risk of bias as they did not utilise blinding (Proesmans 2013; Ratjen 2010; Taccetti 2012; Valerius 1991). The Proesmans 2013 trial compared an inhaled intervention to a combination of inhaled and oral treatment, so blinding of participants and clinicians was not possible; there is no information available as to whether the outcome assessors were blinded. The Ratjen 2010 trial was open‐label, comparing 28 or 56 days of nebulised therapy, and made no attempt at blinding. The Taccetti 2012 trial was also open‐label, comparing 28 days of inhaled colistin with 28 days of TNS; both groups also receiving 28 days of oral ciprofloxacin. Valerius 1991 compared a combination of inhaled and oral treatment to no treatment, so again blinding of participants and clinicians was not possible, and no information is available regarding the outcome assessors.

Incomplete outcome data

We judged seven trials to have a low risk of bias (Gibson 2003; Proesmans 2013; Ratjen 2010; Taccetti 2012; TORPEDO 2020; Treggiari 2011; Valerius 1991). Four trials were analysed on an intention‐to‐treat basis; all four reported data on all participants who were randomised (Gibson 2003; Proesmans 2013; Taccetti 2012; Valerius 1991). In the Ratjen 2010 trial, 65 of the 88 randomised participants were included in the primary outcome (time to recurrence of P aeruginosa). A total of 52 participants were prematurely withdrawn from the trial, but these were approximately evenly distributed across the two treatment groups and reasons were given for each withdrawal. In the Treggiari 2011 trial only two of 306 randomised participants were excluded from the analysis (because they did not receive treatment). In the TORPEDO 2020 trial, 30 of 286 randomised participants, in whom P aeruginosa was not detected after completion of eradication, were excluded from analysis of the primary outcome because they did not have a sample taken at around 15 months. Data were missing from one participant.

We judged three trials to have an unclear risk of bias (ALPINE2 2017; OPTIMIZE 2018; Wiesemann 1998). More than 15% of the participants in ALPINE2 2017 did not complete the study and no information was given on any intention‐to‐treat analysis (ALPINE2 2017). In OPTIMIZE 2018, 33 participants withdrew from the trial (11.8% in the treatment group and 18% in the placebo group); although an intention‐to‐treat analysis included all the participants, it is unclear how the dropout rate has affected the results (OPTIMIZE 2018). Wiesemann 1998 reported that five participants withdrew from the trial after randomisation and only presented baseline data at trial entry for these participants; to date, we have been unable to obtain further outcome data. We therefore analysed this trial on an available‐case basis.

We judged one trial to be at high risk of bias from attrition bias as 35% of the participants discontinued the study after being randomised, five from the intervention group and 13 from the placebo arm (EARLY 2019). The main reason for discontinuing was due to P aeruginosa positivity.

Selective reporting

It is current practice for newer trials to publish a protocol, but we have not been able to locate a published protocol for the Taccetti 2012 trial and have therefore judged this trial to have an unclear risk of bias. We judged three trials to have a high risk of bias (Proesmans 2013; Ratjen 2010; Wiesemann 1998). Although a protocol for the Proesmans 2013 trial was available online, and we were able to confirm from the full paper that all outcomes from the protocol were measured, the paper did not provide actual data for BMI z score, weight z score or frequency of exacerbations and simply reported that none of these changed significantly for trial participants. Ratjen 2010 reported that there were no major short‐term (at three months) or long‐term (at 27 months) changes in spirometry, but did not record the figures for either of the two groups. In addition, only summary statements and no numerical data were provided for weight, height or BMI (Ratjen 2010). Wiesemann 1998 reported no change in spirometric pulmonary function during or after the treatment period, but again reported no data.

We judged seven trials to have a low risk of bias from selective reporting (ALPINE2 2017; EARLY 2019; Gibson 2003; OPTIMIZE 2018; TORPEDO 2020; Treggiari 2011; Valerius 1991). The trial protocol for the EPIC trial was published as a separate paper; primary and secondary outcome measures were clearly described in the protocol and data on all of these outcomes were presented in either the main paper, related papers or in the online supplement (Treggiari 2011). We have compared the 'Methods' sections of the reports from two trials with the 'Results' sections of the same and have not found any evidence of selective reporting (Gibson 2003; Valerius 1991). Trial protocols and online data supplements were available for three trials; all outcomes stated in these were reported in the full papers (EARLY 2019; OPTIMIZE 2018; TORPEDO 2020). One trial has only published results online, but all outcomes stated on the registry appear in the report (ALPINE2 2017).

Other potential sources of bias

We judged one trial to have a high potential risk of bias from other sources (Gibson 2003). Investigators planned to recruit 98 participants, but the trial was stopped early by the Data Monitoring Committee after interim analysis of the first 21 participants showed a statistically significant microbiological effect in favour of the tobramycin‐treated group (Gibson 2003). This trial was supported in part by Chiron, the manufacturer of the inhaled tobramycin (Gibson 2003).

We judged three trials to have an unclear risk of bias (ALPINE2 2017; Proesmans 2013; Ratjen 2010). ALPINE2 2017 was only published as a trial registration document and there was insufficient information for us to adequately assess other potential risks of bias. Proesmans 2013 measured the primary outcome at different time points in different treatment groups: at 28 days in the inhaled tobramycin group and three months in the colistin with ciprofloxacin group. The third trial recruited fewer participants than planned; the total number of planned randomised participants was 100, but 35 from the recruited cohort of 123 were not randomised: 31 because of high P aeruginosa antibody levels (which led the investigators to believe that they were chronically infected with P aeruginosa); one for an adverse event; one where consent was withdrawn; one for a protocol deviation; and one 'other' (unspecified) reason (Ratjen 2010). Therefore, the trial investigators actually randomised 88 participants and the primary outcome was evaluable in 65 of these (Ratjen 2010). The trial results cannot be generalised to a population where anti‐Pseudomonas antibodies are not measured. Furthermore, like the earlier Gibson 2003 trial, this trial was initially supported by Chiron and later Novartis Pharma, the manufacturer of TSI (Ratjen 2010).

We did not identify any potential risks of bias from other sources in seven trials published with full papers and judged these to have a low risk of bias (EARLY 2019; OPTIMIZE 2018; Taccetti 2012; TORPEDO 2020; Treggiari 2011; Valerius 1991; Wiesemann 1998).

One issue which may have unknowingly introduced bias is the fact that individual trial participants can present very differently at baseline with the same diagnosis. For example, one person may present with a positive P aeruginosa culture yet have few symptoms, whilst another may have the symptoms of an exacerbation. Most of the included studies only included "stable" participants and excluded those who had signs and symptoms of an exacerbation (ALPINE2 2017; Gibson 2003; OPTIMIZE 2018; Proesmans 2013; Ratjen 2010), but it is unclear whether definitions were comparable between trials and whether this baseline difference may lead to a difference in the effectiveness of treatments.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9; Table 10

We graded the certainty of evidence for those outcomes included in the summary of findings tables. For the descriptions of these gradings please refer to Table 1 to Table 10.

Please note: in the sections below, the review authors have only presented the outcomes and time points for which they have data or narrative information in order to minimise the length of this text section. Missing outcomes indicate that investigators did not include them or report on them in their trials.

Tobramycin solution for inhalation (TNS) versus placebo

This comparison included three trials with 94 participants (EARLY 2019; Gibson 2003; Wiesemann 1998). The certainty of evidence for this comparison is presented in Table 1.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

The Wiesemann 1998 trial gave a very different dose of TNS (80 mg twice daily) compared to the Gibson 2003 and EARLY 2019 trials (300 mg twice daily). In the EARLY 2019 trial and the Gibson 2003 trial, fewer children in the TNS group had a positive culture after 28 days compared to placebo (OR 0.04, 95% CI 0.01 to 0.15). In the Gibson 2003 trial, fewer children who received TNS had a positive BAL at one month (OR 0.01, 95% CI 0.00 to 0.30), but not at two months (OR 0.21, 95% CI 0.03 to 1.47; Analysis 1.1). Results were not available for all the participants in the Wiesemann 1998 trial, thereby precluding an intention‐to‐treat analysis. Wiesemann 1998 was able to demonstrate a reduction in the odds of a positive culture from the respiratory tract specimen at two months (OR 0.10, 95% CI 0.01 to 0.90); six months (OR 0.06, 95% CI 0.00 to 0.92); and 12 months of treatment (OR 0.02, 95% CI 0.00 to 0.67), but not at one or three months (very low‐certainty evidence; Analysis 1.2).

1.1. Analysis.

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 1: Positive respiratory culture for P aeruginosa (300 mg 2x daily)

1.2. Analysis.

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 2: Positive respiratory culture for P aeruginosa (80 mg 2x daily)

An available‐case analysis of the data presented in the Wiesemann 1998 trial showed that, when combined with the data from the Gibson 2003 and EARLY 2019 trials, there was a reduction in the odds of a positive culture in the treatment group compared to the placebo group both at one month (OR 0.06, 95% CI 0.02 to 0.18; low‐certainty evidence), and with just the Gibson 2003 and Wiesemann 1998 trials at two months (OR 0.15, 95% CI 0.03 to 0.65; Analysis 1.3).

1.3. Analysis.

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 3: Positive respiratory culture for P aeruginosa (combined available case analysis)

A sensitivity analysis following imputation of the missing data to provide best‐case and worst case‐scenarios for the combined analysis showed a range of possible results. The best‐case scenario showed a reduction in the odds of a positive culture of P aeruginosa in the treatment group at both one month (OR 0.06, 95% CI 0.02 to 0.17) and two months (OR 0.14, 95% CI 0.03 to 0.60; Analysis 1.4). Furthermore, these imputed data also showed a difference in favour of TNS at six months (OR 0.04, 95% CI 0.00 to 0.48) and 12 months (OR 0.01, 95% CI 0.00 to 0.26), but not at three months (Analysis 1.4). In the worst‐case scenario the odds of a positive culture was reduced at one month (OR 0.07, 95% CI 0.02 to 0.19) and two months (OR 0.18, 95% CI 0.04 to 0.73), but not at three, six or 12 months when only Wiesemann 1998 reported data (Analysis 1.5).

Secondary Outcomes

1. Mortality

Mortality was not included as an outcome in any of the three trials, but there were no reported deaths during any of the trial periods (EARLY 2019; Gibson 2003; Wiesemann 1998).

3. Spirometric lung function

Wiesemann 1998 reported no change in spirometric pulmonary function during or after the treatment period, but no data were given. Neither remaining trial assessed nor reported on spirometric lung function; most of the participants were too young to perform spirometry reliably (EARLY 2019; Gibson 2003). The certainty of evidence is very low.

4. Growth and nutritional status

Only the trial by Gibson 2003 presented data on weight (kg). There was no evidence of any difference found between the two groups in the change in weight from baseline (trial entry) and subsequent weights measured at one month and two months (Analysis 1.6).

1.6. Analysis.

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 6: Weight (kg) ‐ change from baseline

6. Isolation of other micro‐organisms

Gibson 2003 reported no changes in the prevalence of other micro‐organisms, including multiresistant organisms, cultured from respiratory secretions. Neither of the remaining trials collected data on this outcome (EARLY 2019; Wiesemann 1998).

7. Adverse effects of antibiotics

Two trials reported cough in association with inhalation, but there was no evidence of any difference between groups (OR 0.76, 95% CI 0.10 to 5.77; very low‐certainty evidence; Analysis 1.7). There was no evidence of a difference in serum creatinine levels or auditory threshold between the groups; however, the number of participants were small (Gibson 2003). Wiesemann 1998 reported one withdrawal from the placebo group because of cough but did not report on the presence or absence of cough in other participants.

1.7. Analysis.

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 7: Adverse events

Additional outcomes which have arisen during the review

2. Clinical and radiological scores

Only the Gibson 2003 trial reported modified ShwachmanTreggiari 2011 scores, which were recorded at one month and two months from enrolment and were expressed as both mean scores with SDs and mean change from baseline with SDs. There was no evidence of any differences between the two groups in changes in either mean scores or modified Schwachman scores from baseline at either one month or two months (Analysis 1.8).

1.8. Analysis.

Comparison 1: Inhaled tobramycin (TNS) versus placebo, Outcome 8: Modified Shwachmann score ‐ change from baseline

Inhaled tobramycin (28 days) versus inhaled tobramycin (56 days)

This intervention comparing 28 days TNS with 56 days TNS included one trial of 123 participants, of whom 88 were randomised (Ratjen 2010). The certainty of evidence for this comparison is presented in Table 2.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

This outcome was not evaluated; data were presented in the paper at one month, when participants were all given the initial 28 days of TNS before randomisation and were excluded if they had raised P aeruginosa antibody levels (Ratjen 2010).

b. Time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures

The median time to recurrence was 26.12 months in the 28‐day treatment group and 25.82 months in the 56‐day treatment group. There was no evidence of any differences between groups (HR 0.81, 95% CI 0.37 to 1.76; Analysis 2.1). We deemed the certainty of evidence for this outcome to be low.

2.1. Analysis.

Comparison 2: Inhaled tobramycin (TNS) 28 days versus 56 days, Outcome 1: Time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures

Secondary Outcomes

1. Mortality

There were no deaths reported (Ratjen 2010).

3. Spirometric lung function

The paper presented data in a table for the median change from baseline to three months and to 27 months for FEV₁ % predicted, FVC % predicted and FEF_25-75 % predicted; however, reported data were combined for both the 28‐day and the 56‐day treatment groups. The paper states that there were "no major short‐ or long‐term changes in spirometric parameters observed during the study period" (Ratjen 2010). We assessed the certainty of this evidence to be very low.

4. Growth and nutritional status

The authors did not report any differences in weight, height or BMI and only presented a summary statement indicating that "no significant difference" was found in weight, height or BMI. The trial authors did not provide any data (Ratjen 2010). The certainty of this evidence is very low.

5. Frequency of respiratory exacerbations

Two participants allocated to the 56‐day treatment group were hospitalised on one occasion, each for a pulmonary exacerbation. One of these isolated P aeruginosa and was treated with IV ceftazidime and tobramycin. When entered into the analysis this showed no evidence of any difference between groups (very low‐certainty evidence; Analysis 2.2).

2.2. Analysis.

Comparison 2: Inhaled tobramycin (TNS) 28 days versus 56 days, Outcome 2: Number of respiratory exacerbations

6. Isolation of other micro‐organisms

There were no consistent trends reported in the isolation of non‐P aeruginosa organisms (one isolate only of Stenotrophomonas maltophilia, which was seen in the 28‐day arm) (very low‐certainty evidence).

7. Adverse effects of antibiotics

Adverse events up to three months that were considered possibly or probably related to treatment were reported by 14 participants in each treatment group, with the majority being related to dysphonia in both treatment groups (11% and 14%, respectively) and cough in the 28‐day group (9%). There was no evidence of any differences between treatment groups for any of the reported adverse events at any time point; however, we note that, given the number of different events measured and the increased probability of type I statistical error and spurious group differences, numerical results of these two analyses must be carefully interpreted (Analysis 2.3; Analysis 2.4). The certainty of this evidence is very low.

2.3. Analysis.

Comparison 2: Inhaled tobramycin (TNS) 28 days versus 56 days, Outcome 3: Adverse events (up to 3 months)

2.4. Analysis.

Comparison 2: Inhaled tobramycin (TNS) 28 days versus 56 days, Outcome 4: Adverse events (over 3 months)

Additional outcomes which have arisen during the review

No additional outcomes were reported for this comparison.

Cycled inhaled tobramycin versus culture‐based inhaled tobramycin

This comparison of cycled TNS (with oral ciprofloxacin or placebo) with culture‐based TNS (with oral ciprofloxacin or placebo) included one trial, with 306 participants randomised and data analysed from 304 participants who received treatment (Treggiari 2011). The certainty of evidence for this comparison is presented in Table 3.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

Treggiari 2011 reported that 43 out of 148 children on cycled therapy had one or more isolates of P aeruginosa compared to 67 out of 150 children on culture‐based therapy, giving an effect in favour of cycled therapy (OR 0.51, 95% CI 0.31 to 0.82; Analysis 3.1). We deemed the certainty of this evidence to be moderate. The main trial publication reports an age‐adjusted OR, using generalised estimating equations, with robust variance, specifying a logit link and assuming an independence working correlation (Treggiari 2011). This may explain the difference between the trial publication and the findings of this review.

3.1. Analysis.

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 1: Participants with one or more isolates of P aeruginosa from respiratory tract

Secondary Outcomes

1. Mortality

No deaths were reported in either arm (Treggiari 2011).

3. Spirometric lung function

The included trial reports the mean 70‐week change in FEV₁ % predicted, but there was no evidence of any difference between the two arms (Analysis 3.2) (low‐certainty evidence).

3.2. Analysis.

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 2: FEV₁ % predicted ‐ change from baseline

4. Growth and nutritional status

The Treggiari 2011 trial reports the mean 70‐week change from baseline in weight (kg) for each treatment arm, but there was no evidence of any difference between arms (Analysis 3.3). The trial also reports data for the change from baseline in height (cm) for each arm at the same time point; again the MD did not show any evidence of a difference between groups (Analysis 3.4). We deemed this to be moderate‐certainty evidence.

3.3. Analysis.

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 3: Weight (kg) ‐ change from baseline

3.4. Analysis.

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 4: Height (cm) ‐ change from baseline

5. Frequency of respiratory exacerbations

A primary outcome in the Treggiari 2011 trial was the time to a severe pulmonary exacerbation (i.e. an exacerbation requiring IV antibiotics or hospitalisation or both). The analysis shows no evidence of any difference in time to a severe exacerbation (Analysis 3.5).

Data on the frequency of severe exacerbations during the 70‐week follow‐up period were also presented in the paper. From our analysis, the data indicate no evidence of any difference between groups (Analysis 3.6).

3.6. Analysis.

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 6: Participants with one or more severe pulmonary exacerbations

Treggiari 2011 also reported a secondary outcome of time to pulmonary exacerbation of any severity (including any exacerbation treated with IV, inhaled or oral antibiotics or requiring hospitalisation). The results of our analysis are slightly different to those reported in the paper, but still show no difference in time to any exacerbation (Analysis 3.7).

Finally, the number of exacerbations of any severity was also reported. In our analysis, the OR was not different between cycled and culture‐based therapy (moderate‐certainty evidence; Analysis 3.8).

3.8. Analysis.

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 8: Participants with one or more pulmonary exacerbations (any severity)

6. Isolation of other micro‐organisms

The Treggiari 2011 trial reported the number of participants in each arm with one or more isolates of the emerging pathogen S maltophilia. There was probably no difference between cycled and culture‐based therapy (moderate‐certainty evidence; Analysis 3.9).

3.9. Analysis.

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 9: Participants with new isolates of Stenotrophomonas maltophilia

7. Adverse effects of antibiotics

Regarding the incidence of serious adverse effects, Treggiari 2011 did not report any difference between treatment arms, although adverse events attributable to antibiotic therapy were not recorded separately from adverse events which were unlikely to be related to the study intervention. Our results agree with those reported in the paper (moderate‐certainty evidence; Analysis 3.10).

3.10. Analysis.

Comparison 3: Cycled inhaled tobramycin (TNS) versus culture‐based TNS, Outcome 10: Participants with one or more serious adverse event

Additional outcomes which have arisen during the review

No additional outcomes were reported for this comparison.

Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin therapy

As discussed under Description of studies, the Treggiari 2011 trial randomised participants to cycled versus culture‐based TNS therapy and then to oral ciprofloxacin versus placebo for two weeks with each 28‐day course of TNS. This section presents the comparison of outcomes in the ciprofloxacin and placebo arms. The certainty of evidence for this comparison is presented in Table 4.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

Treggiari 2011 reported that 49 out of 146 children on oral ciprofloxacin had one or more isolates of P aeruginosa compared to 55 out of 152 children on placebo. The data for this outcome show there is probably no difference between treatment groups (OR 0.89, 95% CI 0.55 to 1.44; 1 trial, 298 participants; moderate‐certainty evidence; Analysis 4.1). Age group–adjusted ORs are reported in the trial paper; in our analysis, we did not adjust for age.

4.1. Analysis.

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 1: Participants with one or more isolates of P aeruginosa from respiratory tract

Secondary Outcomes

1. Mortality

No deaths were reported in either arm (Treggiari 2011).

3. Spirometric lung function

The included trial reports the mean 70‐week change in FEV₁ % predicted, but there was no evidence of any difference between the two arms (low‐certainty evidence; Analysis 4.2).

4.2. Analysis.

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 2: FEV₁ % predicted ‐ change from baseline

4. Growth and nutritional status

The Treggiari 2011 trial reports the mean 70‐week change from baseline in weight (kg) for each treatment arm; there was no evidence of any difference between arms (Analysis 4.3). The trial also reports data for the change from baseline in height (cm) for each arm; again there was probably no difference between arms (Analysis 4.4) (moderate‐certainty evidence).

4.3. Analysis.

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 3: Weight (kg) ‐ change from baseline

4.4. Analysis.

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 4: Height (cm) ‐ change from baseline

5. Frequency of respiratory exacerbations

A primary outcome in the Treggiari 2011 trial was the time to a severe pulmonary exacerbation (i.e. an exacerbation requiring IV antibiotics or hospitalisation, or both). Again, for the ciprofloxacin versus placebo comparison, there was no evidence of any difference in time to a severe exacerbation (Analysis 4.5).

Data on the frequency of severe exacerbations during the 70‐week follow‐up period are also presented in the paper. From our analysis, the OR is not different between groups (moderate‐certainty evidence; Analysis 4.6).

4.6. Analysis.

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 6: Participants with one or more severe pulmonary exacerbations

We analysed the outcome 'time to pulmonary exacerbation (any severity)', including any exacerbation treated with IV, inhaled or oral antibiotics or requiring hospitalisation (Analysis 4.7). There was no evidence of any difference between ciprofloxacin and placebo in time to exacerbation (any severity).

Finally, the number of exacerbations of any severity was not different between ciprofloxacin and placebo (Analysis 4.8).

4.8. Analysis.

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 8: Participants with one of more pulmonary exacerbation (any severity)

6. Isolation of other micro‐organisms

In the Treggiari 2011 trial, there was no evidence of any difference between ciprofloxacin and placebo in the number of isolates of S maltophilia (moderate‐certainty evidence; Analysis 4.9).

4.9. Analysis.

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 9: Participants with new isolates of Stenotrophomonas maltophilia

7. Adverse effects of antibiotics

Treggiari 2011 did not report any difference between treatment arms in the incidence of adverse events, although adverse events attributable to antibiotic therapy were not recorded separately from adverse events which were unlikely to be related to the trial intervention. Our analysis showed there is probably no difference between arms in the number of participants with one or more serious adverse events (moderate‐certainty evidence; Analysis 4.10).

4.10. Analysis.

Comparison 4: Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS), Outcome 10: Participants with one or more serious adverse event

Additional outcomes which have arisen during the review

None of the additional outcomes were reported for this comparison.

Oral ciprofloxacin plus inhaled colistin versus inhaled tobramycin

This comparison of oral ciprofloxacin plus inhaled colistin (three months) with TNS (28 days) included only one trial with 58 participants (29 in each treatment group) (Proesmans 2013). The certainty of evidence for this comparison is presented in Table 5.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

At some point in the six months following treatment, P aeruginosa was isolated in 10 out of 29 participants enrolled to the inhaled colistin with oral ciprofloxacin arm compared to 16 out of 29 in the TNS arm (OR 0.43, 95% CI 0.15 to 1.23; Analysis 5.1) and at 24 months (OR 0.76, 95% CI 0.24 to 2.42; Analysis 5.1). There was no evidence of a difference between groups (very low‐certainty evidence).

5.1. Analysis.

Comparison 5: Oral ciprofloxacin and inhaled colistin versus inhaled tobramycin (TNS), Outcome 1: Positive respiratory culture for P aeruginosa

Secondary Outcomes

1. Mortality

There were no deaths in either arm (Proesmans 2013).

3. Spirometric lung function

The median change from baseline in FEV₁ (% predicted) for all the participants was ‐1%. The changes were not reported separately for each treatment arm (Proesmans 2013). We assessed the certainty of this evidence as very low.

4. Growth and nutritional status

Both BMI z score and weight z score were reported not to have changed "significantly" for trial participants as a whole, but numerical data were not reported (very low‐certainty evidence) (Proesmans 2013).

5. Frequency of respiratory exacerbations

The trial authors reported that, during the first six months of follow‐up, there was no difference between the two treatment arms in number of oral antibiotic treatment days. These oral antibiotics were given for symptoms and not because of failed eradication. However, numerical data were not reported (Proesmans 2013).

7. Adverse effects of antibiotics

One participant was reported to have developed a severe cough with TNS, and there were no events in the ciprofloxin and colistin group (Analysis 5.2). No other adverse effects were reported, and we deemed the certainty of evidence to be very low.

5.2. Analysis.

Comparison 5: Oral ciprofloxacin and inhaled colistin versus inhaled tobramycin (TNS), Outcome 2: Adverse events

Additional outcomes which have arisen during the review

None of our additional outcomes were reported for this comparison.

Oral ciprofloxacin plus inhaled colistin versus oral ciprofloxacin plus inhaled tobramycin

This comparison of oral ciprofloxacin plus inhaled colistin with oral ciprofloxacin plus TNS included one trial with 223 participants (Taccetti 2012). The certainty of evidence for this comparison is presented in Table 6.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

In the inhaled colistin plus oral ciprofloxacin group, P aeruginosa was isolated within the first six months from 39 out of 105 participants (37.1%) and in the TNS plus oral ciprofloxacin group from 41 out of 118 participants (34.7%) (Taccetti 2012). When data were analysed, the rate of isolation of P aeruginosa between the two arms was not different (OR 1.11, 95% CI 0.64 to 1.92; Analysis 6.1). At a median follow‐up period of 16 months, P aeruginosa had been isolated from 36 out of 97 participants in the colistin with ciprofloxacin arm for whom data were available and from 24 out of 108 participants in the TNS with ciprofloxacin arm; the two arms did not differ (OR 1.28, 95% CI 0.72 to 2.29; low‐certainty evidence; Analysis 6.1). The trial authors reported that subgroup analyses by gender, age (one to five years; five to 12 years and over 12 years), lung function (FEV₁ % predicted less than or greater than 70%) and participants with first ever isolation of P aeruginosa failed to show any differences between groups (Taccetti 2012).

6.1. Analysis.

Comparison 6: Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin (TNS) plus oral ciprofloxacin, Outcome 1: Positive respiratory culture for P aeruginosa

Secondary Outcomes

1. Mortality

No deaths were reported (Taccetti 2012).

3. Spirometric lung function

Following treatment, after a mean (SD) time of observation of 54 (39) days, the mean (SD) relative change in FEV₁ % predicted from baseline did not differ between groups with 2.15 (8.50)% in the inhaled colistin plus oral ciprofloxacin group compared to 4.55 (11.54)% in the TNS plus oral ciprofloxacin group (Analysis 6.2).

6.2. Analysis.

Comparison 6: Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin (TNS) plus oral ciprofloxacin, Outcome 2: FEV₁ % predicted (relative change from baseline)

6. Isolation of other micro‐organisms

There was an observation that S maltophilia was isolated more frequently in the follow‐up period than before eradication treatment, but our analysis found no evidence of any difference between the two groups during follow‐up for isolation of: S maltophilia,Achromobacter xylosoxidans or Aspergillus species (moderate‐certainty evidence; Analysis 6.3).

6.3. Analysis.

Comparison 6: Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin (TNS) plus oral ciprofloxacin, Outcome 3: Microbiology status (post‐trial)

7. Adverse effects of antibiotics

There were a total of 38 out of 223 randomised participants (17%) who discontinued treatment early; of these, 17 were from the inhaled colistin plus oral ciprofloxacin group and 21 from the TNS plus oral ciprofloxacin group (Analysis 6.4). There were a number of reasons for these discontinuations, including vomiting, photosensitivity, wheeze and pulmonary exacerbation. The certainty of evidence is moderate.

6.4. Analysis.

Comparison 6: Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin (TNS) plus oral ciprofloxacin, Outcome 4: Adverse events leading to trial discontinuation

Additional outcomes which have arisen during the review

None of the additional outcomes were reported for this comparison.

Inhaled tobramycin plus oral azithromycin compared to inhaled tobramycin plus oral placebo

We included one trial (221 participants) comparing TNS plus azithromycin to TNS plus oral placebo (OPTIMIZE 2018). The certainty of evidence for this comparison is presented in Table 7.

Primary outcome

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

Of those participants who were positive for P aeruginosa at baseline and had a culture result available at the end of the first treatment quarter, there was no evidence of any difference in eradication rates between groups (OPTIMIZE 2018). In the azithromycin group, 35 out of 52 (67.3%) participants converted to a negative culture whilst 26 of 39 (66.7%) participants in the placebo group converted to a negative culture (RR 1.01, 95% CI 0.75 to 1.35; low‐certainty evidence; Analysis 7.1).

7.1. Analysis.

Comparison 7: Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo, Outcome 1: Eradication of PA after first treatment quarter

b. Time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures

We found no evidence of any differences between treatment groups in time to recurrence after the first treatment quarter, with 41 out of 103 participants in the azithromycin group and 38 out of 97 participants in the placebo group experiencing a recurrence in the follow‐up period (HR 1.00, 95% CI 0.64 to 1.55; P = 0.99). The authors reported that when the results were adjusted for baseline P aeruginosa status, the overall odds of recurrence in the azithromycin group were slightly higher than the placebo group although not "significant" (OR 1.33, 95% CI 0.80 to 2.23; P = 0.27) (OPTIMIZE 2018).

Secondary Outcomes

1. Mortality

No deaths were reported in either treatment group (OPTIMIZE 2018).

3. Spirometric lung function

Data reported in the paper showed no evidence of any difference between groups in mean change in FEV₁ % predicted over the 18‐month period (MD ‐1.71%, 95% CI ‐7.76 to 4.34; P = 0.384; low‐certainty evidence). The authors also reported that there was no difference between groups in any of the other spirometry parameters, but the data were not presented (OPTIMIZE 2018).

4. Growth and nutritional status

There was an improvement in weight (kg) in the azithromycin group compared to the placebo group (MD 1.27 kg, 95% CI 0.01 to ‐2.52; P = 0.046; moderate‐certainty evidence), but no evidence of any difference between groups in height (MD 0.97 cm, 95% CI ‐0.73 to 2.68; P = 0.36; moderate‐certainty evidence) (OPTIMIZE 2018).

5. Frequency of respiratory exacerbations

Time to next exacerbation was decreased in the azithromycin group compared to the placebo group (HR 0.56, 95% CI 0.37 to 0.83; P = 0.004). There was a 44% decreased risk of exacerbation associated with azithromycin. The number of participants experiencing an exacerbation by the end of the study was lower in the azithromycin group compared to the placebo group (RR 0.75, 95% CI 0.56 to 1.00; moderate‐certainty evidence; Analysis 7.2).

7.2. Analysis.

Comparison 7: Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo, Outcome 2: Number of participants experiencing an exacerbation

Need for additional antibiotics

There was no evidence of any difference between groups in the need for additional IV antibiotics (RR 1.01, 95% CI 0.60 to 1.69; Analysis 7.3), inhaled antibiotics (RR 1.35, 95% CI 0.31 to 5.87; Analysis 7.3) or oral antibiotics (RR 0.89, 95% CI 0.74 to 1.08; Analysis 7.3) (OPTIMIZE 2018).

7.3. Analysis.

Comparison 7: Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo, Outcome 3: Number of participants requiring additional antibiotics during the study

Hospitalisations

We found no evidence of any difference between groups in the number of participants requiring hospitalisation during the trial (RR 0.97, 95% CI 0.59 to 1.59; Analysis 7.4) (OPTIMIZE 2018).

7.4. Analysis.

Comparison 7: Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo, Outcome 4: Number of hospitalisations

6. Isolation of other micro‐organisms

The emergence of other pathogens during the study was found to be comparable between groups, and numbers were small. We found moderate‐certainty evidence for the pathogens reported, which included methicillin‐resistant Staphylococcus aureus (MRSA) (RR 0.83, 95% CI 0.35 to 1.94; Analysis 7.5), Burkholderia cepacia (RR 0.32, 95% CI 0.01 to 7.71; Analysis 7.5), A xylosoxidans (RR 1.59, 95% CI 0.39 to 6.47; Analysis 7.5), S maltophilia (RR 1.65, 95% CI 0.72 to 3.76; Analysis 7.5), Haemophilus influenzae (RR 1.13, 95% CI 0.58 to 2.21; Analysis 7.5) and NTM (RR 0.67, 95% CI 0.05 to 9.66; Analysis 7.5) (OPTIMIZE 2018).

7.5. Analysis.

Comparison 7: Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo, Outcome 5: Isolation of other micro‐organisms at any time point post‐baseline

7. Adverse effects of antibiotics

There was no evidence of differences in the occurrence of serious adverse events between the treatment groups (moderate‐certainty evidence). The number of participants experiencing any adverse event is shown in Analysis 7.6. We found no evidence of differences for gastro‐intestinal disorders, general disorders and administration site conditions, metabolism and nutrition disorders, infections and infestations, nervous system disorders, renal and urinary disorders or respiratory, thoracic and mediastinal disorders (OPTIMIZE 2018). The investigators also stated that no participants experienced temporary or permanent sensorineural hearing loss in either group and there were no differences between groups in abnormal electrocardiograms (OPTIMIZE 2018).

7.6. Analysis.

Comparison 7: Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo, Outcome 6: Adverse events

Oral ciprofloxacin and inhaled colistin versus no treatment

This comparison included only one trial with 26 participants (Valerius 1991). The certainty of evidence for this comparison is presented in Table 8.

Primary outcome

None of our primary outcomes were reported.

Secondary Outcomes

7. Adverse effects of antibiotics

Valerius 1991 did not describe cough specifically, but reported that there were no adverse effects in either group. Certainty of evidence was very low.

Additional outcomes which have arisen during the review

1. Time to chronic infection

We defined this as the presence of P aeruginosa in each monthly sputum sample for six consecutive months or the presence of precipitating antibodies to P aeruginosa, or both. From the data provided for the Valerius 1991 trial, it was possible to calculate the proportion of participants in each group who were defined as chronically infected with P aeruginosa from respiratory secretions at three, six, 12 and 24 months. The odds of being chronically infected with P aeruginosa were reduced in the treatment group compared to the placebo group after 24 months (OR 0.12, 95% CI 0.02 to 0.79; Analysis 8.1). We found no evidence of a difference between the two groups at the other time points. No other trials in the review used this outcome measure to express their findings.

8.1. Analysis.

Comparison 8: Oral ciprofloxacin and inhaled colistin versus no treatment, Outcome 1: Proportion colonised with P aeruginosa

Inhaled AZLI for 14 days plus placebo for 14 days compared to inhaled AZLI for 28 days

Only one trial with 149 participants compared 14 days of AZLI followed by 14 days of placebo to 28 days of AZLI (ALPINE2 2017). To date, the results of the trial are only available via the online trials registry; the certainty of evidence for this comparison is presented in Table 9.

1. Eradication of P aeruginosa from the respiratory tract

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

In the 28‐day period after treatment, 55.9% of participants in the intervention group (AZLI 14 days) had negative P aeruginosa cultures compared to 63.4% in the control group (MD ‐7.50%, 95% CI ‐24.80 to 9.80; 1 trial, 139 participants; very low‐certainty evidence; Analysis 9.1). The CIs are wide, suggesting there may be little real difference between groups (ALPINE2 2017).

9.1. Analysis.

Comparison 9: AZLI 14 days plus placebo 14 days versus AZLI 28 days, Outcome 1: Proportion of participants with negative cultures at 28 days

b. Time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures

The trial also reported the time to recurrence of P aeruginosa over a follow‐up period of 108 weeks and stated that in the intervention group the median time to recurrence was 19.3 months. The median value for the control group was not available as the calculated percentiles of event rate were not reached (ALPINE2 2017).

Secondary Outcomes

1. Mortality

No deaths were reported in either group during the follow‐up period of the trial (ALPINE2 2017).

7. Adverse effects of antibiotics

The trial did not specifically report adverse effects of antibiotics, but did report on the number of participants in each group who experienced serious adverse events (ALPINE2 2017). Five out of 74 (6.76%) participants in the AZLI 14‐day group experienced adverse events compared to four out of 75 (5.33%) in the AZLI 28‐day group (RR 1.27, 95% CI 0.35 to 4.53; Analysis 9.2).

9.2. Analysis.

Comparison 9: AZLI 14 days plus placebo 14 days versus AZLI 28 days, Outcome 2: Adverse Events

Additional outcomes which have arisen during the review

No additional outcomes were reported for this comparison.

IV ceftazidime and tobramycin compared with oral ciprofloxacin (both treatment regimens in conjunction with three months nebulised colistin)

One trial, which included 286 adults and children, is included in this comparison (TORPEDO 2020). The certainty of evidence for this comparison is presented in Table 10.

Primary outcome

a. Clearance of P aeruginosa from BAL, sputum or oropharyngeal cultures

In the IV group, 55 out of 125 participants had eradicated P aeruginosa at three months compared to 68 of 130 participants in the oral group. This showed no difference in the chance of achieving eradication at three months and maintaining it to 15 months between the group receiving IV compared to the oral antibiotic group when given inhaled colistin alongside (RR 0.84, 95% CI 0.65 to 1.09; P = 0.18; Analysis 10.1; high‐certainty evidence).

10.1. Analysis.

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 1: Eradication of P aeruginosa from respiratory samples at 3 months and remaining free

b. Time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures

The trial investigators reported data showing no evidence of any difference in the time to the next recurrence of P aeruginosa between the intravenous and the oral group (HR 1.31, 95% CI 0.93 to 1.85; P = 0.12) (TORPEDO 2020).

Secondary Outcomes

1. Mortality

There were no deaths in either group throughout the trial (TORPEDO 2020).

2. Quality of life

A total of 134 out of 285 participants completed CFQ‐R quality of life questionnaires (only for children aged six and over). We found no evidence of any differences between treatment groups across any of the domains in the questionnaire. The trial also reported no difference between groups with regard to the median number of days of absenteeism (P = 0.62 for carer responses and P = 0.26 for participant completed responses) (TORPEDO 2020).

3. Spirometric lung function

There was no difference between IV treatment and oral treatment with respect to FEV₁ % predicted (MD 2.08%, 95% CI ‐0.81 to 4.97; Analysis 10.2) or FEF_25-75 % predicted (MD 3.46%, 95% CI ‐3.35 to 10.27; Analysis 10.4). At the end of the trial, FVC % predicted was higher in the IV treatment group (MD 3.14%, 95% CI 0.31 to 5.97; high‐certainty evidence; Analysis 10.3) (TORPEDO 2020).

10.2. Analysis.

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 2: FEV₁ % predicted

10.4. Analysis.

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 4: FEF_25-75

10.3. Analysis.

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 3: FVC % predicted

4. Growth and nutritional status

Our analysis showed no difference between groups for any of the growth and nutritional status indicators: height‐for‐age z score (MD ‐0.03, 95% CI ‐0.13 to 0.07; high‐certainty evidence; Analysis 10.5); weight‐for‐age z score (MD ‐0.02, 95% CI ‐0.15 to 0.11; high‐certainty evidence; Analysis 10.6); and BMI z score (paediatric) (MD 0.01, 95% CI ‐0.12 to 0.14; high‐certainty evidence; Analysis 10.7). There were a lot fewer adults recruited into the trial (n = 15), and for those participants a different scoring method, BMI (kg/m²), was used to reflect growth and nutritional status. This outcome measure also showed no evidence of any difference between treatment groups, BMI (kg/m²) in adults (MD ‐0.74, 95% CI ‐3.40 to 1.92; high‐certainty evidence; Analysis 10.8) (TORPEDO 2020).

10.5. Analysis.

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 5: Growth and nutritional status: height‐for‐age z score

10.6. Analysis.

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 6: Growth and nutritional status: weight‐for‐age z score

10.7. Analysis.

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 7: Growth and nutritional status: BMI z score (paediatric)

10.8. Analysis.

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 8: Growth and nutritional status: BMI (kg/m²; adult)

5. Frequency of respiratory exacerbations

Number of participants experiencing an exacerbation by the end of the study

Over the course of the study 38 out of 137 participants in the IV group experienced an exacerbation compared with 52 out of 156 in the oral antibiotic group; however, when analysed there was no difference seen between the groups (RR 0.78, 95% CI 0.55 to 1.10; high‐certainty evidence; Analysis 10.9).

10.9. Analysis.

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 9: Frequency of exacerbations: number of participants who experienced an exacerbation

Hospitalisations

In the period after initial eradication, fewer participants were admitted to hospital in the IV group compared to the oral group (RR 0.69, 95% CI 0.50 to 0.95; Analysis 10.10). The trial also reported on the median number of days in hospital during the three‐month treatment phase (median in both groups was zero days (range 0 to 29 days for the IV group (n = 135) and (range 0 to 15 days for the oral group (n = 143)) (P = 0·066). In the 12‐month post‐treatment phase, the median number of days in hospital was also zero for both groups (range 0 to 69 days for IV treatment group (n = 129) and 0 to 64 days for the oral treatment group (n = 136); P = 0·005) (TORPEDO 2020).

10.10. Analysis.

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 10: Frequency of exacerbations: number of participants admitted to hospital

6. Isolation of other micro‐organisms

There was no difference between the oral and IV groups in the isolation of other pathogens, including MRSA (MD 2.07, 95% CI 0.39 to 11.14; high‐certainty evidence; Analysis 10.11); B cepacia (MD 0.51, 95% CI 0.10 to 2.76; high‐certainty evidence; Analysis 10.11); Candida spp (MD 1.04, 95% CI 0.78 to 1.40; high‐certainty evidence; Analysis 10.11); and Aspergillus spp (MD 0.72, 95% CI 0.38 to 1.37; high‐certainty evidence; Analysis 10.11) (TORPEDO 2020).

10.11. Analysis.

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 11: Isolation of other organisms: number of participants isolating a positive culture during 15‐month study period

7. Adverse effects of antibiotics

There was probably no difference in serious adverse effects (RR 0.97, 95% CI 0.43 to 2.16; moderate‐certainty evidence; Analysis 10.12) or non‐serious adverse effects (RR 0.97, 95% CI 0.75 to 1.24; moderate‐certainty evidence; Analysis 10.12) between groups, except for upper respiratory tract infections (URTIs) where there were fewer incidences in the oral antibiotic treatment group (RR 6.37, 95% CI 1.44 to 28.21; moderate‐certainty evidence; Analysis 10.12). No serious adverse reactions to antibiotics were reported in either group (TORPEDO 2020).

10.12. Analysis.

Comparison 10: IV ceftazidime with tobramycin versus oral ciprofloxacin, Outcome 12: Adverse events

Additional outcomes

3. Cost‐effectiveness

Overall, oral treatment was less costly than IV treatment (including intervention costs). The incremental difference in mean costs was GBP 5939 lower (95% CI –7107 to –4666) after adjusting for baseline covariates (TORPEDO 2020).

Discussion

Summary of main results

Our review includes 11 trials (with data from 1449 participants) of antibiotic strategies for eradicating P aeruginosa infection in people with CF, conducted over a period of over 30 years. Each trial used a different intervention; up to three trials could be combined in meta‐analyses for some outcomes, but the majority of comparisons had only one or two studies per outcome. In one trial, an early interim‐analysis was performed due to slow accrual (Gibson 2003).

Inhaled tobramycin versus placebo

This comparison included three trials with 94 participants (EARLY 2019; Gibson 2003; Wiesemann 1998). The trials administered two different doses of TNS; Wiesemann 1998 used 80 mg twice daily compared to the Gibson 2003 trial and the EARLY 2019 trial, which both used 300 mg twice daily.

There may be a slight improvement in eradication with TNS (low‐certainty evidence). The trials with the higher dose reported that fewer participants were still positive for P aeruginosa in respiratory secretions in the participants receiving antibiotics than from those receiving placebo at one month and two months; combined data also showed antibiotic treatment may lead to fewer positive respiratory culture for P aeruginosa at one month (OR 0.06, 95% CI 0.02 to 0.18; 3 trials, 89 participants; low‐certainty evidence; Analysis 1.3) and two months (OR 0.15, 95% CI 0.03 to 0.65; 2 trials, 38 participants; Analysis 1.3) after the start of treatment (Gibson 2003; Wiesemann 1998). We are uncertain whether there is a reduction in the odds of a positive culture at 12 months (OR 0.02, 95% CI 0.00 to 0.67; 1 trial, 12 participants; Analysis 1.2).

We are uncertain whether there is any difference in spirometric lung function, growth and nutrition or isolation of other micro‐organisms between those on TNS and those on placebo. We are also uncertain whether there is any difference between groups in adverse effects.

Inhaled tobramycin (28 days) versus inhaled tobramycin (56 days)

The Ratjen 2010 trial (n = 88) ran from November 2003 until January 2008 and compared 28‐day and 56‐day treatment with TNS; there was no difference in time to next isolation between treatments (HR 0.81, 95% CI 0.37 to 1.76; low‐certainty evidence; Analysis 2.1).

We are uncertain whether there was any difference between treatments in terms of spirometric lung function, growth and nutrition, frequency of exacerbations or isolation of other micro‐organisms. Similarly, there were no differences in adverse effects between groups (Ratjen 2010).

Cycled inhaled tobramycin versus culture‐based inhaled tobramycin

The Treggiari 2011 trial was the largest trial of P aeruginosa eradication in CF reported so far, randomising and reporting data on 304 children (aged one to 12 years). The trial used a complex, four‐arm design, comparing cycled with culture‐based treatment with TNS and also additional oral ciprofloxacin versus placebo. The trial was adequately powered for its two primary outcome measures (time to severe pulmonary exacerbation and proportion of P aeruginosa positive cultures). Our analysis found cycled therapy may lead to fewer isolates of P aeruginosa from the respiratory tract (OR 0.51, 95% CI 0.31 to 0.82; moderate‐certainty evidence; Analysis 3.1), although the trial publication reported age‐adjusted OR and found no difference between groups.

Cycled therapy may make no difference to FEV₁ % predicted (low‐certainty evidence) and probably makes no difference to growth and nutrition outcomes, weight and height (moderate‐certainty evidence). There is probably no difference in the frequency of pulmonary exacerbations (OR 0.75, 95% 0.48 to 1.17; moderate‐certainty evidence; Analysis 3.8). Similarly, there is probably no difference in isolation of other micro‐organisms (S maltophilia) (OR 1.18, 95% CI 0.65 to 2.12; moderate‐certainty evidence; Analysis 3.9). There is probably no difference between cycled and culture‐based therapy in adverse effects (moderate‐certainty evidence; Analysis 3.10).

Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin therapy

The Treggiari 2011 trial (304 children randomised) looked at the effect of adding ciprofloxacin or placebo to cycled and culture‐based therapy and found that there is probably no difference made by adding either ciprofloxacin or placebo in eradicating P aeruginosa (OR 0.89, 95% CI 0.55 to 1.44; 297 participants; moderate‐certainty evidence; Analysis 4.1). Adding ciprofloxacin may make little difference to spirometric lung function (low‐certainty evidence; Analysis 4.2) and probably no difference in terms of growth and nutritional outcomes (moderate‐certainty evidence; Analysis 4.3; Analysis 4.4). There was also probably no difference in terms of the frequency of exacerbations (moderate‐certainty evidence; Analysis 4.8), isolation of other organisms (moderate‐certainty evidence; Analysis 4.9) or adverse effects (moderate‐certainty evidence; Analysis 4.10).

Oral ciprofloxacin and inhaled colistin versus inhaled tobramycin

One trial (58 participants (29 in each treatment group)) compared oral ciprofloxacin with inhaled colistin (three months) with TNS (28 days) (Proesmans 2013).

Our analysis found no difference between groups in terms of eradication of P aeruginosa at up to six months (OR 0.43, 95% CI 0.15 to 1.23; very low‐certainty evidence; Analysis 5.1) or at 24 months (OR 0.76, 95% CI 0.24 to 2.42; very low‐certainty evidence; Analysis 5.1). (Proesmans 2013). The numbers of participants in each group were too low to allow comparisons of superiority between the two eradication regimens to be made. A further possible cause of the low eradication rate in this trial may be that participants were recruited if they had been free of P aeruginosa for at least six months (with negative microbiology samples for at least six months), which is shorter than the 12‐month P aeruginosa‐free interval used by the Leeds definition of 'Pseudomonas‐free' (Lee 2003).

We are uncertain whether there is any difference in spirometric lung function, growth and nutrition or adverse effects (Proesmans 2013).

Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin plus oral ciprofloxacin

The Taccetti 2012 trial (223 participants) compared TNS with oral ciprofloxacin to inhaled colistin with oral ciprofloxacin, both treatments given over 28 days. At 16 months, there may be no difference in positive respiratory cultures (OR 1.28, 95% CI 0.72 to 2.29; low‐certainty evidence; Analysis 6.1). The included participants had been free of P aeruginosa for at least six months, again at variance with the Leeds definition of Pseudomonas‐free (Lee 2003).

Inhaled tobramycin with oral ciprofloxacin compared to inhaled colistin with oral ciprofloxacin may make no difference to spirometric lung function or isolation of other organisms. There is probably no difference in adverse effects between groups.

Inhaled tobramycin plus oral azithromycin compared to inhaled tobramycin plus oral placebo

One trial (221 participants) compared adding oral azithromycin or placebo to TNS (OPTIMIZE 2018). Investigators found that adding oral azithromycin may make no difference to the number of participants eradicated after three months of treatment (RR 1.01, 95% CI 0.75 to 1.35; low‐certainty evidence; Analysis 7.1). This analysis only included 91 participants who were positive for P aeruginosa at baseline and had a culture result available at the end of the first treatment quarter. The paper reports that there were also no differences in time to recurrence.

At the 18‐month follow‐up, the results reported in the paper showed that adding oral azithromycin may make no difference to FEV₁ % predicted (MD ‐1.71%, 95 % CI ‐7.76 to 4.34; P = 0.384; low‐certainty evidence). The paper reported that there was probably a slight improvement in weight in the oral azithromycin group at the 18‐month follow‐up (MD 1.27 kg, 95 % CI 0.01 to ‐2.52; P = 0.046; moderate‐certainty evidence), although no difference in height (MD 0.97 cm, 95 % CI ‐0.73 to 2.68; P = 0.36; moderate‐certainty evidence) (OPTIMIZE 2018). Adding oral azithromycin probably resulted in fewer participants experiencing an exacerbation by the end of the trial (RR 0.75, 95 % CI 0.56 to 1.00; moderate‐certainty evidence; Analysis 7.2). There was no difference between groups in the occurrence of serious adverse effects (moderate‐certainty evidence; Analysis 7.6).

Oral ciprofloxacin and inhaled colistin versus no treatment

This comparison included only one trial with 26 participants (Valerius 1991). None of our primary outcomes were reported in this comparison but an additional outcome arising during the review (time to chronic infection) was reported. There was no difference in the odds of being chronically infected with P aeruginosa in the treatment group compared to the no treatment group after 12 months (OR 0.17, 95% CI 0.03 to 1.09; Analysis 8.1) (Valerius 1991). No adverse effects were reported in either group.

Inhaled AZLI for 14 days plus placebo for 14 days compared to inhaled AZLI for 28 days

The ALPINE2 2017 trial (149 participants aged between 28 days and 17 years old) compared the effectiveness of 14 days of AZLI followed by 14 days of placebo (74 participants) to 28 days of AZLI (75 participants) in eradicating P aeruginosa. We are uncertain whether 14 days of AZLI improves the eradication of P aeruginosa compared to 28 days as the certainty of evidence has been assessed as very low (very low‐certainty evidence; Analysis 9.1). We are also uncertain whether 14 days of AZLI altered the time to recurrence of P aeruginosa over 108 weeks median time to recurrence for the control group was not available.

There was no difference in adverse reactions to either treatment group (Analysis 9.2). No additional outcomes were reported.

Intravenous ceftazidime with tobramycin compared with oral ciprofloxacin (both treatment regimens in conjunction with three months nebulised colistin)

The TORPEDO 2020 trial (286 participants aged 28 days old and above) compared the use of 14 days of intravenous ceftazidime and tobramycin (n = 137) to a 12‐week course of oral ciprofloxacin (n = 149) for eradicating P aeruginosa; both regimens were combined with 12 weeks of inhaled colistimethate sodium. The investigators found that intravenous ceftazidime made little to no difference to the chance of achieving eradication of P aeruginosa at three months and little to no difference in sustaining eradication at 15 months compared to the oral treatment group (RR 0.84, 95% CI 0.65 to 1.09; P = 0.18; Analysis 10.1; high‐certainty evidence). There was also no difference in time to next isolation of P aeruginosa between both treatment groups (HR 1.31, 95% CI 0.93 to 1.85; P = 0.12).

The paper reported that intravenous therapy made little to no difference in the frequency of respiratory exacerbations (RR 0.78, 95% CI 0.55 to 1.10; high‐certainty evidence; Analysis 10.9) and to the isolation of other pathogens including: MRSA (MD 2.07, 95% CI 0.39 to 11.14; high‐certainty evidence; Analysis 10.11); B cepacia (MD 0.51, 95% CI 0.10 to 2.76; high‐certainty evidence; Analysis 10.11); Candida spp (MD 1.04, 95% CI 0.78 to 1.40; high‐certainty evidence; Analysis 10.11); and Aspergillus spp (MD 0.72, 95% CI 0.38 to 1.37; high‐certainty evidence; Analysis 10.11) compared to the oral group.

During follow up the investigators reported that by the end of the trial, those in the intravenous treatment had a higher FVC% predicted compared to the oral group (MD 3.14%, 95% CI 0.31 to 5.97; high‐certainty evidence; Analysis 10.3). There was probably no difference in either serious or non‐serious adverse effects between the groups (moderate‐certainty evidence; Analysis 10.12) except there was a reduction in upper respiratory tract infections in the oral antibiotic treatment group (RR 6.37, 95% CI 1.44 to 28.21; moderate‐certainty evidence; Analysis 10.12).

Overall completeness and applicability of evidence

The aim of antibiotic therapy for early P aeruginosa infection in CF should be both successful and sustained eradication of the pathogen and improvement in (or slowing in the rate of decline of) clinical parameters, whilst minimising adverse effects and the isolation of new micro‐organisms. If P aeruginosa is successfully eradicated, but there is no measurable clinical benefit, it is likely that current measures of clinical status are not sufficiently sensitive or that the duration of follow‐up is too short to show a difference.

There are differences in the type and dose of drug administered to the treatment groups in the three placebo‐controlled trials of TNS (EARLY 2019; Gibson 2003; Wiesemann 1998). In the Wiesemann 1998 trial, tobramycin injectable solution was administered by nebuliser, at a low dose (80 mg twice daily) for a longer duration (12 months); whereas Gibson 2003 and EARLY 2019 used TSI TOBI^® (now marketed by Novartis) at a higher dose (300 mg twice daily) for a shorter duration (28 days). This is a potential source of heterogeneity between the trials.

Two trials included participants who were Pseudomonas‐naive and those that had not isolated P aeruginosa for at least six months (Proesmans 2013; Taccetti 2012), which is at variance with the 12‐month definition proposed by Lee to define a person as 'Pseudomonas‐free' (Lee 2003). We were not able to extract IPD for those participants who fit this longer definition of Pseudomonas‐free. The Treggiari 2011 trial required participants to have been free of P aeruginosa for at least two years. The TORPEDO 2020 trial also recruited those who were Pseudomonas‐naive; participants who had previously isolated P aeruginosa had to have been negative for at least 12 months.

The TORPEDO 2020 trial was the only trial using an intravenous therapy. The dose of oral ciprofloxacin used in those randomised to oral therapy was twice daily 15 mg/kg or 20 mg/kg (to a maximum of 750 mg) depending on age. This dose was broadly in keeping with previous trials (Proesmans 2013; Taccetti 2012; Treggiari 2011; Valerius 1991). The dose of inhaled colistimethate sodium was also broadly similar between these trials.

The ALPINE2 2017 trial was the only trial to use AZLI, and compared the efficacy of 14 days of AZLI followed by 14 days of placebo versus 28 days of AZLI. The primary endpoint was a negative respiratory culture 28‐days post‐treatment. Long‐term data were not presented. There was no comparison with another anti‐pseudomonal agent made.

Eradication of isolates of P aeruginosa is believed to be easier in people with CF with recent onset of infection, in particular in those who have non‐mucoid isolates of P aeruginosa. We could only include the first treatment period of the EARLY 2019 trial (which was a cross‐over trial). However, data from the second treatment period of this trial suggest that a 28‐day delay in initiating treatment for P aeruginosa substantially reduces the chance of successful eradication (from 76% to 48% success). Three trials included in this review recruited adults (Ratjen 2010; Taccetti 2012; TORPEDO 2020), suggesting that early P aeruginosa infection can be eradicated from adults as well as from children, and therefore adults should be included in future studies.

Most of the trials included in this review required patients to be clinically stable prior to recruitment. The results may not be applicable to people with CF who have a pulmonary exacerbation and simultaneously require eradication of P aeruginosa.

Finally, it should be noted that some of the trials were conducted between 10 and 20 years ago and the results may be less applicable to people with CF today, particularly following the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators into routine clinical care.

Quality of the evidence

The quality of the trials was variable, with important deficiencies identified in some. For example, in four out of the 11 included trials we judged there to be a high risk of bias from a lack of blinding of participants and clinicians; in two of these trials the different interventions used in the treatment and control groups precluded blinding (Proesmans 2013; Valerius 1991) and two trials were open‐label with no attempt made at blinding. We also judged there to be a high risk of bias due to selective reporting in three of the trials, which only reported summary statements with no actual data for a number of outcomes (Proesmans 2013; Ratjen 2010; Wiesemann 1998).

While we generally judged there to be a low risk of bias due to incomplete outcome data, there was incomplete follow‐up of a number of participants in one of the older and smaller trials (Wiesemann 1998). The absence of these data has complicated the combined analysis of the three trials that compare TNS with placebo (EARLY 2019; Gibson 2003; Wiesemann 1998); two trials were analysed on an intention‐to‐treat basis (EARLY 2019; Gibson 2003) and another on an available‐case basis (Wiesemann 1998). A sensitivity analysis based on best‐ and worst‐case scenarios demonstrated similar results to the available‐case analysis. The available‐case analysis revealed a reduction in the odds of a positive culture for P aeruginosa in the group treated with TNS when compared to the odds in the placebo group at both one and two months from the start of treatment (Wiesemann 1998). One trial only published limited results on a trial registry database; the limited information did not allow us to properly judge the risk of bias due to incomplete outcome data (ALPINE2 2017).

The Gibson 2003 trial was stopped early because of evidence of significant treatment effect. It has been suggested that the results of RCTs stopped early for benefit should be interpreted with caution, particularly when the number of events is small (Montori 2005).

In the Ratjen 2010 trial, the authors wished to enrol 120 participants in order to randomise 100 participants. They succeeded in recruiting 123 individuals, of whom 88 were randomised and 65 could be included in the analysis of the primary outcome (time to recurrence of P aeruginosa). This trial is potentially subject to bias because of the exclusion of non‐randomised individuals, including 31 people in whom there were elevated antibody titres to P aeruginosa.

The relationship between the presence of P aeruginosa in secretions from the upper respiratory tract and the isolation of P aeruginosa from the lower respiratory tract is inconsistent. Reporting of the presence of organisms in respiratory secretions is difficult to standardise, dependent on the sampling methods used and on the number of samples taken. The trials included in this review used a heterogeneous mix of methods to sample respiratory secretions from both the lower and upper respiratory tracts. No two trials used the same methods and more than one method was used in two trials. There was no subgroup analysis based on sampling method in any of the trials, probably owing to relatively small numbers of participants in individual trials. Wiesemann 1998 used a combination of oropharyngeal swabs and sputum samples, whereas Gibson 2003 used BAL fluid. Proesmans 2013 used sputum, throat swab and BAL. The Taccetti 2012 study did not describe the technique used for culture collection. The Treggiari 2011 trial enrolled younger children and used oropharyngeal swabs or sputum samples. The TORPEDO 2020 trial collected cough swabs from their younger participants and sputum samples (both induced and non‐induced) in older children. There were also a small number of samples taken from oropharyngeal aspirate (n = 1), nasopharyngeal aspirate (n = 1), cough plate (n = 9) and BAL (n = 3) (TORPEDO 2020). Armstrong 1996 has shown that the results of oropharyngeal specimens are poorly predictive of the presence of organisms in the lower respiratory tract. Valerius 1991 relied on sputum samples which can be of poor quality in younger children.

The certainty of evidence ranged from high to very low, based on GRADE criteria. We graded most evidence as moderate or low quality (see Table 1 to Table 10).

The main reasons for downgrading the certainty of evidence included risk of bias within the trials, as discussed above, but we also downgraded the certainty of evidence due to indirectness where the results were not applicable to all participants. This was mainly where trials included only adults or only children. We were not able to relate the results to the whole population to answer our review question. Five of our comparisons reported results only in children (Table 1; Table 2; Table 5; Table 7; Table 8). We also downgraded the results where there was imprecision caused by wide CIs around the effect and small participant numbers, or both. Due to the fact that most of our comparisons included only one trial, there were limited opportunities to combine results in a meta‐analysis to increase the sample size and the certainty of the evidence. We also downgraded for imprecision where there were no numerical results available, and we were uncertain of the evidence provided by these trials.

Potential biases in the review process

The original review stated that trials would be included only where eradication begins within two months of isolation of P aeruginosa. In a post hoc change, this has now been altered to include those where eradication has been initiated up to six months since isolation. Whilst prompt treatment of new P aeruginosa infection is recommended (Smyth 2014), there is no robust evidence for a specific time limit for initiation of treatment.

The review now also includes two distinct groups of individuals ‐ those who are Pseudomonas‐naive and those who are Pseudomonas‐free.

Agreements and disagreements with other studies or reviews

We are not aware of any other studies or reviews which assess specific eradication treatment.

Authors' conclusions

Implications for practice.

More children with cystic fibrosis (CF) cleared Pseudomonas aeruginosa from their respiratory secretions up to three months after commencing antibiotic therapy aimed at eradicating the organism from their respiratory tract when compared to placebo. This effect may last for several months. This review has not established any improvement in clinical outcome measures following treatment. The small numbers of participants in some trials and the short duration of follow‐up mean that this review may have insufficient statistical power to detect changes in these clinical outcomes. However, there are many observational studies which have shown a decline in clinical status once chronic P aeruginosa infection occurs and so clinical benefit from eradication is likely. There was no difference in the rate of common adverse effects detected. An increased incidence of the emerging pathogen Stenotrophomonas maltophilia was seen after eradication treatment in two trials, but there was no difference between regimens (Taccetti 2012; Treggiari 2011).

We found that nebulised antibiotics (or a combination of nebulised and oral antibiotics) were better than no treatment in treating early infection with P aeruginosa, which was eliminated in the majority of individuals. We found that intravenous antibiotics did not confer an added benefit over the use of oral antibiotics. Eradication may be sustained in the short term. We were unable to determine whether there is an associated clinical benefit to people with CF, though data from observational studies suggest that benefit is likely. Overall, there is insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early P aeruginosa infection in CF. However, from this review we have deduced that eradication treatment should be given promptly following a positive P aeruginosa culture, that treatment to eradicate P aeruginosa is better than not treating and that intravenous treatment for eradication does not give additional benefit.

Implications for research.

Whilst there is evidence that eradication treatment is more effective than placebo or no treatment, there is limited evidence to help the clinician choose which regimen to use. There remains an urgent need for well‐designed and well‐executed trials, comparing eradication regimens; however, the quality of the trials recently published within peer‐reviewed journals show significant improvement. Where possible, future trials should evaluate whether eradication results in appreciable clinical benefit to people with CF, without causing them harm. Trials should also explore the influence of prior infection with P aeruginosa ('Pseudomonas‐free' compared to 'Pseudomonas‐naive') and whether there is an advantage in early institution of therapy (within weeks rather than within months). This might be accomplished using a stratified trial design. Consideration should be given to appropriate outcome measures, particularly spirometric lung function and possibly also including measurement of lung clearance index in younger children, nutritional status, socio‐economic outcomes (including quality of life) and duration of follow‐up. There is also a need to standardise which outcome measures are used, how microbiological respiratory samples are obtained and the definition for successful eradication of P aeruginosa as a result of an intervention. Long‐term follow‐up trials with careful clinical and bacteriological surveillance are required, with a standardisation of follow‐up length. These trials will be challenging to design and deliver. Randomisation should include two active treatments that are both believed to be effective and safe, and would still need to recruit a sufficient number of participants to show differences in efficacy with adequate power. Adults as well as children should be included in such trials.

What's new

Date	Event	Description
2 June 2023	New search has been performed	A search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register identified 56 new references potentially eligible for inclusion in the updated review. We have included four new studies (20 new references) at this update (ALPINE2 2017; EARLY 2019; OPTIMIZE 2018; TORPEDO 2020), two of these were previously listed as ongoing (EARLY 2019; TORPEDO 2020). There were eight additional references to four already included studies (Proesmans 2013; Ratjen 2010; Taccetti 2012; Treggiari 2011). We excluded five new studies (14 new references) (Bustamante 2014; Di Cicco 2014; Frost 2021; Hansen 2015; Herrmann 2017). We added 14 new references to 11 already excluded studies (Clancy 2013; Elborn 2015; Flume 2015a; Flume 2015b; Goss 2009; Konstan 2011; Mainz 2014; Prayle 2013; Ramsey 1999; Rietschel 2009; Schuster 2013). We identified three new studies (one reference each) which are ongoing (EUCTR2007‐003868‐22‐FR; EUCTR2011‐006171‐19‐IT; EUCTR2015‐003881‐96‐IT).
2 June 2023	New citation required and conclusions have changed	Three new authors have joined the team: Sherie Smith, Nicola J Rowbotham and Alexander Yule. After the inclusion of four new studies, we have updated our conclusions as follows: "We found that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained for up to two years. There is insufficient evidence to determine whether antibiotic strategies for eradicating early P aeruginosa 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 has shown that intravenous ceftazidime with tobramycin is not superior to oral ciprofloxacin. 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."

History

Protocol first published: Issue 2, 2003
Review first published: Issue 1, 2006

Date	Event	Description
19 April 2017	New citation required but conclusions have not changed	We have not been able to include data from any new trials at this update and our conclusions remain the same.
18 April 2017	New search has been performed	A search of the Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register identified 56 unique references possibly eligible for inclusion in the review. One reference (conference abstract) was a new ongoing trial (EARLY 2019). Four references were added to an already included trial (Treggiari 2011). Eight references were added to four already excluded trials: four references (Goss 2009); one reference (Mainz 2014); two references (Wainwright 2011a); and one reference (Wainwright 2011b). Ten new trials (47 references) were excluded (Elborn 2015; Flume 2015a; Flume 2015b; Flume 2016; Geller 2011; Konstan 2011; Konstan 2015; Ruddy 2013; Stass 2013; Stockmann 2015). Two references described two of the trials and one reference described three of the trials ‐ these references are linked multiple times, once to each of the trials they describe. Summary of findings tables have been included in the review at this update.
29 October 2014	New search has been performed	A search of the Group's CF Register identified 117 references for possible inclusion in the review. Three references have been added to an already included trial (Proesmans 2013). One trial, known as the ELITE trial, has been moved from 'Ongoing studies' to 'Included studies' and the reference to the full publication added; this trial has provided a comparison of duration of intervention not previously available for inclusion (Ratjen 2010). A further trial also previously listed as ongoing with the study ID Ramsey 2005 (also known as the EPIC trial) has been included with 11 new references (Treggiari 2011). One new trial, with nine references has been included (Taccetti 2012). A total of 22 new trials (97 references) have been excluded: one reference each (Alothman 2005; Goss 2009; Prayle 2013; Postnikov 2007; Wainwright 2011b); two references each (Alothman 2002; Kenny 2009; Mainz 2014; Schelstraete 2010; Tramper‐Stranders 2009); three references each (Coates 2011; Geller 2007; Mazurek 2012; Rietschel 2009); four references each (Retsch‐Bogart 2008; Trapnell 2012); five references each (Clancy 2013; Konstan 2010); six references each (Oermann 2009; Schuster 2013); 10 references (Retsch‐Bogart 2009); and 32 references (Ramsey 1999). Two trials previously listed as 'Awaiting classification' have now been excluded (Latzin 2008; Lenoir 2007). One additional reference has been added to a previously excluded study (Wainwright 2011a) The full paper to an abstract already listed as 'Awaiting Classification' has now been published and added to the existing study ID while we await clarification regarding participants from the authors (Noah 2010). One new trial (with a single reference) has been added to 'Ongoing studies' (TORPEDO 2020). There have been three post hoc changes to the review at this update: we now include participants who have received treatment within six months of the first isolation of P. aeruginosa (previously not more than two months); we now allow trials where all patients receive some eradication therapy before randomisation which reflects current recommended 'standard of care' and consequent trial design; we have added cost as an outcome measure, as cost‐effectiveness has become increasingly important in CF care.
29 October 2014	New citation required but conclusions have not changed	This review has been updated, but the conclusions remain the same.
10 June 2009	New citation required but conclusions have not changed	From the 2009 update of this review, the lead author Dr Damian Wood has stepped down and is no longer involved in the review. The new lead author is Dr Simon Langton Hewer.
10 June 2009	New search has been performed	A new search of the Group's CF Register identified 14 new references. We have included one new study with one reference (Proesmans 2013) and excluded two new studies with three new references (Postnikov 2000; Steinkamp 2007). Three studies with a total of five references are listed as 'Awaiting classification' until we are able to obtain further details (Latzin 2008a; Lenoir 2007a; Noah 2007). We have added five references to the two ongoing studies: one reference to Ramsey 2005a and four references to Ratjen 2006a.
12 November 2008	Amended	Converted to new review format.
13 November 2007	New search has been performed	The search identified four new trials; two of which have been excluded (Gibson 2007; Griese 2002); and two of which are still ongoing (Ramsey 2005a; Ratjen 2006a).
13 November 2007	Amended	The review authors have addressed some comments from the CFGD Group's medical statistician within this update.
15 November 2006	Feedback has been incorporated	The review now contains the response from the authors to feedback regarding the necessity of further trials received through The Cochrane Library Feedback system.

Appendices

Appendix 1. Search strategies for online trial registries

Trial registry	Search terms	Date of last search
ClinicalTrials.gov (clinicaltrials.gov)	Advance search Condition or disease: cystic fibrosis Other terms: Pseudomonas aeruginosa AND (eradication OR eradicate) Study type: Interventional (Clinical Trials)	6 April 2022
WHO International Clinical Trials Registry Platform (WHO ICTRP)	Basic search cystic fibrosis AND pseudomonas aeruginosa AND (eradication OR eradicate) Trial phase: All	6 April 2022
International Standard Randomised Controlled Trial Number (ISRCTN) Registry (ISRCTN)	Basic search cystic fibrosis AND pseudomonas aeruginosa AND (eradication OR eradicate)	6 April 2022

Data and analyses

Comparison 1. Inhaled tobramycin (TNS) versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Positive respiratory culture for P aeruginosa (300 mg 2x daily)	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1.1 At 1 month	2	72	Odds Ratio (M‐H, Fixed, 95% CI)	0.04 [0.01, 0.15]
1.1.2 At 2 months	1	21	Odds Ratio (M‐H, Fixed, 95% CI)	0.21 [0.03, 1.47]
1.2 Positive respiratory culture for P aeruginosa (80 mg 2x daily)	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.2.1 At 1 month	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.2.2 At 2 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.2.3 At 3 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.2.4 At 6 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.2.5 At 12 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.3 Positive respiratory culture for P aeruginosa (combined available case analysis)	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.3.1 At 1 month	3	89	Odds Ratio (M‐H, Fixed, 95% CI)	0.06 [0.02, 0.18]
1.3.2 At 2 months	2	38	Odds Ratio (M‐H, Fixed, 95% CI)	0.15 [0.03, 0.65]
1.4 Positive respiratory culture for P aeruginosa (combined) ‐ best case	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.4.1 At 1 month	3	90	Odds Ratio (M‐H, Fixed, 95% CI)	0.06 [0.02, 0.17]
1.4.2 At 2 months	2	39	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.03, 0.60]
1.4.3 At 3 months	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.02, 1.16]
1.4.4 At 6 months	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.04 [0.00, 0.48]
1.4.5 At 12 months	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.01 [0.00, 0.26]
1.5 Positive respiratory culture for P aeruginosa (combined) ‐ worst case	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.5.1 At 1 month	3	90	Odds Ratio (M‐H, Fixed, 95% CI)	0.07 [0.02, 0.19]
1.5.2 At 2 months	2	39	Odds Ratio (M‐H, Fixed, 95% CI)	0.18 [0.04, 0.73]
1.5.3 At 3 months	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.36 [0.05, 2.77]
1.5.4 At 6 months	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 1.83]
1.5.5 At 12 months	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.36 [0.05, 2.77]
1.6 Weight (kg) ‐ change from baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.6.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.6.2 At 2 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.7 Adverse events	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.7.1 Cough	2	72	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.10, 5.77]
1.8 Modified Shwachmann score ‐ change from baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.8.1 At 1 month	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.8.2 At 2 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 2. Inhaled tobramycin (TNS) 28 days versus 56 days.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Time to next isolation of P aeruginosa from BAL, sputum or oropharyngeal cultures	1		Hazard Ratio (IV, Fixed, 95% CI)	Totals not selected
2.2 Number of respiratory exacerbations	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.2.1 Until recurrence of P. aeruginosa	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3 Adverse events (up to 3 months)	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.1 Cough	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.2 Productive cough	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.3 Haemoptysis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.4 Rhinitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.5 Sinusitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.6 Nasopharyngitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.7 Tonsilitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.8 Oropharyngeal pain	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.9 Dysphonia	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.10 Headache	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.11 URTI	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.12 Lung disorder	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.13 Bronchitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.14 P. aeruginosa infection	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.15 Influenza	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.16 Otitis media	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.17 Deafness	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.18 Drug level increased	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.19 Pyrexia	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.20 Vomiting	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3.21 Varicella	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4 Adverse events (over 3 months)	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.1 Cough	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.2 Productive cough	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.3 Haemoptysis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.4 Rhinitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.5 Sinusitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.6 Nasopharyngitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.7 Tonsilitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.8 Oropharyngeal pain	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.9 Dysphonia	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.10 Headache	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.11 URTI	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.12 Lung disorder	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.13 Bronchitis	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.14 P. aeruginosa infection	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.15 Influenza	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.16 Otitis media	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.17 Deafness	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.18 Drug level increased	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.19 Pyrexia	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.20 Vomiting	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4.21 Varicella	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 3. Cycled inhaled tobramycin (TNS) versus culture‐based TNS.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Participants with one or more isolates of P aeruginosa from respiratory tract	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected
3.2 FEV₁ % predicted ‐ change from baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.2.1 Mean duration of 70 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.3 Weight (kg) ‐ change from baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.3.1 Mean duration of 70 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.4 Height (cm) ‐ change from baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.4.1 Mean duration of 70 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.5 Time to severe pulmonary exacerbation	1		Hazard Ratio (IV, Fixed, 95% CI)	Totals not selected
3.6 Participants with one or more severe pulmonary exacerbations	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected
3.7 Time to pulmonary exacerbation (any severity)	1		Hazard Ratio (IV, Fixed, 95% CI)	Totals not selected
3.8 Participants with one or more pulmonary exacerbations (any severity)	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected
3.9 Participants with new isolates of Stenotrophomonas maltophilia	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected
3.10 Participants with one or more serious adverse event	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

Comparison 4. Ciprofloxacin versus placebo added to cycled and culture‐based inhaled tobramycin (TNS).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Participants with one or more isolates of P aeruginosa from respiratory tract	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected
4.2 FEV₁ % predicted ‐ change from baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.2.1 Mean duration of 70 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.3 Weight (kg) ‐ change from baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.3.1 Mean duration of 70 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.4 Height (cm) ‐ change from baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.4.1 Mean duration of 70 weeks	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.5 Time to severe pulmonary exacerbation	1		Hazard Ratio (IV, Fixed, 95% CI)	Totals not selected
4.6 Participants with one or more severe pulmonary exacerbations	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected
4.7 Time to pulmonary exacerbation (any severity)	1		Hazard Ratio (IV, Fixed, 95% CI)	Totals not selected
4.8 Participants with one of more pulmonary exacerbation (any severity)	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected
4.9 Participants with new isolates of Stenotrophomonas maltophilia	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected
4.10 Participants with one or more serious adverse event	1		Odds Ratio (IV, Fixed, 95% CI)	Totals not selected

Comparison 5. Oral ciprofloxacin and inhaled colistin versus inhaled tobramycin (TNS).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Positive respiratory culture for P aeruginosa	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.1.1 In first 6 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.1.2 At 24 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.2 Adverse events	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.2.1 Severe cough	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 6. Inhaled colistin plus oral ciprofloxacin versus inhaled tobramycin (TNS) plus oral ciprofloxacin.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Positive respiratory culture for P aeruginosa	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.1.1 In first 6 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.1.2 At end of follow‐up (median 16 months)	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.2 FEV₁ % predicted (relative change from baseline)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
6.2.1 At mean 54 days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
6.3 Microbiology status (post‐trial)	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.3.1 Stenotrophomonas maltophilia	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.3.2 Achromobacter xylosoxidans	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.3.3 Aspergillus species	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.4 Adverse events leading to trial discontinuation	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.4.1 Vomiting	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.4.2 Photosensitivity	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.4.3 Wheeze	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.4.4 Pulmonary exacerbation during early eradication treatment	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.4.5 Lack of compliance	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 7. Inhaled tobramycin (TNS) plus oral azithromycin versus TNS plus oral placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Eradication of PA after first treatment quarter	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.2 Number of participants experiencing an exacerbation	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.2.1 At 18 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.3 Number of participants requiring additional antibiotics during the study	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.3.1 IV antibiotics	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.3.2 Inhaled antibiotics	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.3.3 Oral antibiotics	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.4 Number of hospitalisations	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5 Isolation of other micro‐organisms at any time point post‐baseline	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5.1 MRSA	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5.2 B cepacia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5.3 A xylosoxidans	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5.4 S maltophilia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5.5 H influenzae	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.5.6 NTM	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.1 Any adverse event during the study	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.2 Serious adverse events ‐ GI disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.3 Serious adverse events ‐ general disorders and administration site conditions	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.4 Serious adverse events ‐ metabolism and nutrition disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.5 Serious adverse events ‐ infections and infestations	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.6 Serious adverse events ‐ nervous system disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.7 Serious adverse events ‐ renal and urinary disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6.8 Serious adverse events ‐ respiratory, thoracic, and mediastinal disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 8. Oral ciprofloxacin and inhaled colistin versus no treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Proportion colonised with P aeruginosa	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.1.1 At 3 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.1.2 At 6 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.1.3 At 12 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.1.4 At 24 months	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 9. AZLI 14 days plus placebo 14 days versus AZLI 28 days.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Proportion of participants with negative cultures at 28 days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
9.2 Adverse Events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 10. IV ceftazidime with tobramycin versus oral ciprofloxacin.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Eradication of P aeruginosa from respiratory samples at 3 months and remaining free	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.1.1 At 15 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.2 FEV1 % predicted	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.2.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.3 FVC % predicted	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.3.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.4 FEF25-75	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.4.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.5 Growth and nutritional status: height‐for‐age z score	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.5.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.6 Growth and nutritional status: weight‐for‐age z score	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.6.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.7 Growth and nutritional status: BMI z score (paediatric)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.7.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.8 Growth and nutritional status: BMI (kg/m2; adult)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.8.1 At 15 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.9 Frequency of exacerbations: number of participants who experienced an exacerbation	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.9.1 At 15 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.10 Frequency of exacerbations: number of participants admitted to hospital	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.11 Isolation of other organisms: number of participants isolating a positive culture during 15‐month study period	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.11.1 MRSA	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.11.2 B cepacia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.11.3 Candida spp	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.11.4 Aspergillus spp	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.1 Any non‐serious adverse event (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.2 Non‐serious adverse events: cough (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.3 Non‐serious adverse events: URTI (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.4 Non‐serious adverse events: productive cough (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.5 Serious adverse events (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.6 Serious adverse events: GI disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.7 Serious adverse events: general disorders and administration site conditions (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.8 Serious adverse events: Hepatobiliary disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.9 Serious adverse events: Infections and infestations (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.10 Serious adverse events: nervous system disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.11 Serious adverse events: psychiatric disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.12 Serious adverse events: renal and urinary disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.13 Serious adverse events: respiratory, thoracic and mediastinal disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.14 Serious adverse events: skin and subcutaneous tissue disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.15 Serious adverse events: surgical and medical procedures (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10.12.16 Serious adverse events: vascular disorders (number of participants)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Characteristics of studies

Characteristics of included studies [ordered by study ID]

ALPINE2 2017.

Study characteristics
Methods	Double‐blind RCT. Parallel design. Duration of study: 28 day treatment period, primary endpoint 28 days post‐treatment, followed up for 108 weeks. Multicentre trial carried out in Europe, Israel and the USA.
Participants	149 children and adolescents with CF (age range 28 days to < 18 years) and new onset lower respiratory tract culture positive for P aeruginosa Intervention group (AZLI 14 days + placebo), n = 74 Age, mean (SD): 7.3 (5.34) years. Sex (males/females): 35/39 (47% female). Comparatorgroup (AZLI 28 days), n = 75 Age, mean (SD): 6.5 (4.91) years. Sex (males/females): 33/42 (44% female). No further details of baseline characteristics given.
Interventions	Intervention group: 75 mg/mL AZLI 3 times daily for 14 days followed by placebo to match AZLI 3 times daily for 14 days. Both AZLI and matched placebo were delivered via the PARI Altera® nebuliser system. Comparator group: 75 mg/mL AZLI 3 times daily for 28 days via the PARI Altera® nebuliser system. In both groups, participants younger than 2 years received interventions via the SmartMask® Baby; participants aged 2 years up to 6 years via the SmartMask Kids®; and participants over 6 years via the nebuliser mouthpiece.
Outcomes	Primary outcome Proportion of participants with P aeruginosa‐negative cultures through 28 days post‐treatment. Secondary outcomes Time from P aeruginosa eradication to recurrence over a 108‐week post‐treatment follow‐up period. Proportion of participants with P aeruginosa‐negative cultures through 28 days post‐treatment in the 14‐day treatment group versus historical pooled data for P aeruginosa eradication at 28 days post‐treatment in participants treated with TNS. Time to P aeruginosa recurrence for a subgroup of participants matching the population in the TNS ELITE study over a 108‐week post‐treatment follow‐up period. Primary eradication is defined as all P aeruginosa‐negative cultures through 28 days post‐AZLI treatment. Cultures will be obtained at week 16 and then at 12‐week intervals during the follow‐up time frame.
Notes	Sponsored by Gilead Sciences, Inc, USA (commercial). The primary objective of this study is to evaluate the safety and efficacy of a 14‐day course versus a 28‐day course of AZLI 75 mg 3 times a day in participants with new onset P aeruginosa respiratory tract colonisation or infection as determined by P aeruginosa eradication over a 28‐day post‐treatment follow‐up period.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Methods state that selection was randomised, but no description further description.
Allocation concealment (selection bias)	Unclear risk	Methods states that allocation was "double blinded" but no further details provided.
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blind study. The protocol states that the participants and the investigator were blinded.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	More than 15% of participants were unable to complete the primary endpoint (25/74 in the AZLI 14 days arm and 18/75 in the AZLI 28 days arm). Information on intention‐to‐treat analysis not provided.
Selective reporting (reporting bias)	Low risk	Trial outcomes reported in the European Trials Registry and all outcomes stated are present within the report.
Other bias	Unclear risk	The document reviewed is a trial registration document and does not contain contextualisation or detailed explanations of the results. Therefore, information is missing to allow for accurate assessment of risk of bias.

EARLY 2019.

Study characteristics
Methods	Double‐blind RCT. First treatment phase is double‐blind and parallel. The remaining arms of the trial are cross‐over in design and will not be included in our analysis. Multicentre: 15 centres across nine countries (Canada, Egypt, France, Germany, Greece, Hungary, Italy, Russia and Switzerland). Duration of trial: the parallel phase is a 28‐day treatment period.
Participants	51 children aged 3 months to < 7 years Inclusion criteria Confirmed diagnosis of CF. Early lower respiratory tract infection with P aeruginosa (either first‐ever positive or first positive after at least a year of negative cultures). Exclusion criteria Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics. Administration of loop diuretics within 7 days prior to study drug administration. Other protocol‐defined inclusion/exclusion criteria may apply. Age Median age (range) in months was 39.0 (6.0 to 82.0). TNS Median (range) 41.0 (7 to 82) Group ≥ 3 months to < 4 years: n = 16 (61.5%) Group ≥ 4 years to < 7 years: n = 10 (38.5%) Placebo Median (range) 36.0 (6 to 82) Group ≥ 3 months to < 4 years: n = 16 (64.0%) Group ≥ 4 years to < 7 years: n = 9 (36.0%) Sex Female n (%) TNS: 15 (57.7) Placebo: 17 (68.0) Disease status Episode ofP aeruginosainfection – first infection n (%) TOBI: 24 (92.3) Placebo: 23 (92.0) Episode ofP aeruginosainfection – re‐infection TNS: 2 (7.7) Placebo: 2 (8.0) Current use of short‐acting bronchodilator n (%) TNS: 13 (50.0) Placebo: 15 (60.0) Current use of long‐acting bronchodilator n (%) TNS: 2 (7.7) Placebo: 2 (8.0) Current use of inhaled corticosteroids n (%) TNS: 4 (15.4) Placebo: 5 (20.0) Body weight (kg) mean (SD) TNS: 14.5 (4.5) Placebo: 13.7 (4.1)
Interventions	Intervention group: TNS 300mg/5ml tobramycin for inhalation given twice a day for 28 days Participants randomised to TNS received the investigational treatment for 28 days 2 x daily. At the end of 1st treatment cycle, participants who were positive for P aeruginosa entered the optional open‐label phase of the trial and received TNS for 28 days 2x daily. Participants who were negative for P aeruginosa at the end of 1st treatment cycle and agreed to participate in the cross‐over treatment period received placebo for 28 days 2 x daily (2nd treatment cycle). Comparator group: placebo/TNS Participants randomised to placebo group received 0.9 % saline (NaCl) for 28 days 2x daily. Cross‐over phase (not included in our analysis): At the end of 1st treatment cycle, participants who were positive for P aeruginosa entered the open‐label phase of the study and received TNS for 28 days 2x daily. Participants who were negative for P aeruginosa at the end of 1st treatment cycle and agreed to participate in the cross‐over treatment period (optional) received the opposite treatment from the treatment they were randomised to in the first phase.
Outcomes	Primary outcome Percentage of participants P aeruginosa‐free after completion of the 1st treatment cycle (Day 29) as assessed by sputum or throat swab cultures Secondary outcomes Percentage of participants free from P aeruginosa 28 days after termination of the 2nd treatment cycle (Day 91) as assessed by sputum or throat swab cultures. Percentage of participants P aeruginosa‐free at termination of the double‐blind period (Day 91) as assessed by sputum or throat swab cultures. Safety variables ‐ adverse events
Notes	Completion date: June 2015 (final data collection date for primary outcome measure). Sponsors: Novartis Pharmaceuticals
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised 1:1 but no details given as to how the randomisation was performed.
Allocation concealment (selection bias)	Unclear risk	No details given regarding allocation concealment.
Blinding (performance bias and detection bias) All outcomes	Low risk	The first treatment arm was double‐blind but no further details given. It was not stated whether outcome assessors were blinded to allocation, but as the primary outcome is presence of P aeruginosa in sputum it is unlikely that lack of blinding would affect the outcome assessment.
Incomplete outcome data (attrition bias) All outcomes	High risk	All 51 received the intended treatment but 18 participants discontinued during the double‐blind phase (5 from the TOBI arm and 13 from the placebo arm. 35% discontinued. Most discontinued due to P aeruginosa positivity. One participant in the placebo arm discontinued due to an SAE.
Selective reporting (reporting bias)	Low risk	All outcomes stated in the trial registration document were reported in the paper.
Other bias	Low risk	No other bias identified.

Gibson 2003.

Study characteristics
Methods	Double‐blind RCT. Placebo‐controlled. Parallel design. Duration: 28 days. Multicentre based in USA.
Participants	21 participants with a recent positive oropharyngeal culture and isolation of P aeruginosa from BAL at study entry. Age: 6 months to 6 years. Gender: 11 males, 10 females.
Interventions	Intervention group: TNS 300 mg 2 x daily for 28 days. Control group: placebo inhalations.
Outcomes	Eradication of P aeruginosa, nutritional status, modified Shwachman score, adverse effects.
Notes	Oropharyngeal cultures performed at entry and on days 14, 28, 42 and 56 of the study. BAL from the same lobar segment on entry and day 28. Enrolment was discontinued due to an interim analysis, precipitated by poor accrual of participants, which showed a statistically significant microbiological effect of treatment.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as an RCT stratified by centre and age (≦ 36 months; > 36 months), but the method of generation of allocation sequence was not stated.
Allocation concealment (selection bias)	Unclear risk	Did not report how allocation was concealed.
Blinding (performance bias and detection bias) All outcomes	Low risk	Reported as double‐blind, but paper did not provide any details regarding who was blinded or the method of blinding. We received the following helpful response from trial authors, regarding placebo. Active: Preservative free tobramycin sulfate, 60 mg/mL in 5 mL excipient (1/4 normal saline, pH 6.0) in low density polyethylene plastic ampoules inside a foil pouch (PathoGenesis Corporation). Placebo: 5 mL of vehicle with 1.25 mg of quinine sulfate added as a flavouring agent, packaged identically. PathoGenesis Corporation were responsible for the manufacture of the tobramycin and placebo for inhalation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Analysed on an intention‐to‐treat basis. Reported data on all participants who were randomised. There were no dropouts reported.
Selective reporting (reporting bias)	Low risk	No evidence of selective reporting found.
Other bias	High risk	Study was stopped early by the Data Monitoring Committee after recruitment of 21 from an anticipated 98 participants because of statistically significant treatment effect in favour of the tobramycin group. Study received sponsorship support from Chiron, manufacturer of tobramycin for inhalation as used in the study.

OPTIMIZE 2018.

Study characteristics
Methods	RCT. Parallel group. Multicentre study carried out in 45 Cystic Fibrosis Foundation accredited centres in USA. Duration of study: 18 months.
Participants	221 children randomised (intervention group n = 110; placebo group n = 111) Inclusion criteria Documentation of a CF diagnosis as evidenced by 1 or more clinical features consistent with the CF phenotype or positive CF newborn screening result for IRT, IRT/DNA or IRT/IRT and 1 or more of the following criteria: sweat chloride ≥ 60 milliequivalent (mEq)/L by quantitative by pilocarpine iontophoresis test; two well‐characterised mutations in the CFTR gene; abnormal NPD (change in NPD in response to a low chloride solution and isoproteronol of less than ‐ 5 mV); documented new positive oropharyngeal, sputum or lower respiratory tract culture for P aeruginosa within 30 days of the baseline visit (Visit 1), defined as: a) first lifetime documented P aeruginosa positive culture; or b) P aeruginosa recovered after at least a 2‐year history of P aeruginosa negative respiratory cultures (≥ 1 culture/year); clinically stable with no evidence of any significant respiratory symptoms at the baseline visit requiring IV anti‐pseudomonal antibiotics, oxygen supplementation, and/or hospitalisation as determined by the study physician; written informed consent obtained from participant or participant's legal representative (and assent when applicable) and ability for participant to comply with the requirements of the study. Baseline characteristics TNS plus oral azithromycin Age, mean (SD): 7.1 (5.1) years. Sex, males/females: 55/55. FEV1 % predicted, mean (SD): 94.9 (18.0) % predicted. P aeruginosa naive n (%): 64 (58.2). P aeruginosa free n (%): 46 (41.8). Height, mean (SD): 116.0 (32.3) cm. Weight, mean (SD): 26.7 (17.5) kg. TNS plus placebo Age, mean (SD): 6.8 ( 5.0) years. Sex, males/females: 62/49. FEV1 % predicted, mean (SD): 93.4 (16.1) % predicted. P aeruginosa naive n (%): 65 (58.6). P aeruginosa free n (%): 46 (41.4). Height, mean (SD): 114.5 (30.6) cm. Weight, mean (SD): 25.1 (16.2) kg. Group differences at baseline Chronic hypertonic saline and dornase alfa use was slightly higher among azithromycin participants (40.9% and 70.9% of 110 participants, respectively) compared with placebo participants (31.5% and 59.5% of 111 participants). Use of these two therapies was mainly in the older age groups (data not shown).
Interventions	Intervention group: TNS 300 mg, twice daily for 28 days when respiratory cultures are found positive for P aeruginosa at study visits for 18 months; plus oral azithromycin 10 mg/kg up to a maximum of 500 mg per dose given 3 times a week for 18 months. Placebo group: TNS 300 mg, twice daily for 28 days when respiratory cultures are found positive for P aeruginosa at study visits for 18 months; plus oral placebo given 3 times a week for 18 months.
Outcomes	18‐month study period with 8 follow‐up visits, baseline, day 21, weeks 13, 26, 39, 52, 65, and 78. Primary outcome Time to a protocol‐defined pulmonary exacerbation requiring oral, inhaled, or IV antibiotics, using a prespecified definition. Secondary outcomes Time to P aeruginosa recurrence after the first quarter of therapy. Safety (as measured by adverse events, electrocardiogram, and audiologic monitoring). Frequency of exacerbations. Frequency of P aeruginosa‐positive cultures. Rates of antibiotic use. Hospitalisations. Change in nutritional status (height, weight). Lung function (in participants over 4 years of age). Patient/parent‐reported respiratory symptoms (using CRISS)
Notes	Funding source & study sponsor: Bonnie Ramsey supported by NIH grants. Additional support was provided through NIH clinical and translational science awards National Institutes of Health/National Heart, Lung, and Blood Institute (NHLBI). Study drug provided by Pfizer, Inc and by Novartis Pharmaceuticals Corp; study compressors & nebulisers provided by PARI Respiratory Equip, Inc.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised using the Medita Rave and Balance systems. An adaptive randomisation (dynamic allocation based on minimisation) was used to ensure equal representation in each study arm for each age strata. Participants were randomised in a 1:1 ratio.
Allocation concealment (selection bias)	Low risk	Allocation to treatment arm was done via the computer‐generated algorithm and the allocation code was not known to the site research staff. To randomise a new participant study personnel completed an electronic case report from with baseline data in the Medidata Rave system, which assigned a participant to study arm.
Blinding (performance bias and detection bias) All outcomes	Low risk	The study was double‐blind and treatment arms were unknown to participants, parents/legal guardians and site research staff. Azithromycin and placebo were manufactured to be identical in appearance and taste‐matched. Packaging and labelling of treatments was identical.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	221 children were randomised to azithromycin or placebo. 33 participants withdrew from the study (13 (11.8 %) in the azithromycin group; 20 (18 %) in the placebo group). A total of 21 (19.1 %) and 5 (4.5 %) azithromycin participants and 19 (17.1 %) and 9 (8.1 %) of placebo participants temporarily or permanently discontinued the study drug, respectively. All participants were included in the intention‐to‐treat analysis.
Selective reporting (reporting bias)	Low risk	No selective reporting identified. All outcomes stated in the protocol were reported in the study paper.
Other bias	Low risk	No other sources of bias identified.

Proesmans 2013.

Study characteristics
Methods	RCT. Parallel design. Duration: 3 months. Single centre based in Europe.
Participants	58 children with CF, all with new isolation of P aeruginosa (sputum or cough swabs). Age, median (IQR): 9 (4.7 ‐ 13.1) years. Sex, males/females: 31 / 27. FEV1 % predicted, median: at inclusion 98% predicted.
Interventions	Intervention group (n = 29): Inhaled TNS 300 mg 2x daily for 28 days. Control group (n = 29): 3 months combination therapy with inhaled colistin (2 MU 2x daily) plus oral ciprofloxacin (10 mg/kg 3x daily).
Outcomes	Primary outcome Eradication of P aeruginosa at the end of treatment. Secondary outcomes Time to P aeruginosa relapse Antibodies IgG FEV1 BMI P aeruginosa status at 2‐year follow‐up
Notes	Participants were then switched to the other arm or treated with IV antibiotics if clinically indicated. Funding source not stated
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised in blocks of 10. No description given of method of randomisation, nor of any stratification.
Allocation concealment (selection bias)	Unclear risk	Did not report how allocation was concealed.
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding not possible for participants and clinicians as treatments compared were inhaled versus inhaled and oral. No details regarding whether outcome assessors were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention‐to‐treat analysis on all 58 randomised participants.
Selective reporting (reporting bias)	High risk	Protocol published on ClinicalTrials.gov (identifier: NCT01400750). All prespecified outcomes reported. BMI z score, weight z score and frequency of exacerbations were reported not to have changed significantly for trial participants, but numerical data are not reported.
Other bias	Unclear risk	Primary outcome was assessed at end of treatment which was different for the 2 treatment groups 28 days for TIS participants versus 3 months for colistin/ciprofloxacin participants.

Ratjen 2010.

Study characteristics
Methods	RCT. Parallel design. Duration: 27 months. Multicentre (21 centres) based in Europe (Germany, France, Spain, Austria, UK, Netherlands).
Participants	123 participants with CF and a first or early infection with P aeruginosa (88 randomised ‐ 31 participants not randomised because of high P aeruginosa antibody titres and 4 for other reasons). Participants were excluded if they had signs or symptoms of acute pulmonary disease. 28‐day TNS Group Age, mean (SD): 8.7 (7.2) years. Sex: 26 (58%) males, 19 (42%) females. FEV1 % predicted, mean (SD): 80.2 (18.9) % predicted. 56‐day TNS Group Age, mean (SD): 8.7 (10.5) years Sex: 22 (51%) males, 21 (49%) females FEV1 % predicted, mean (SD): 87.0 (19.2) % predicted.
Interventions	Intervention group (n = 45): TNS 300 mg 2 x daily for 28 days, then stopped treatment. Comparator group (n = 43): TNS 300 mg 2 x daily for 28 days, then randomised to a further 28 days TNS (56 days in total).
Outcomes	Primary outcome Median time to recurrence of any strain of P aeruginosa. Secondary outcomes Proportion of participants free of P aeruginosa 1 month after the end of treatment. Number and length of hospital admissions for respiratory indications. Occurrence of other pathogens. Changes in FEV1, FVC & FEF25-75. Weight. Height. BMI
Notes	Also known as ELITE trial.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised, but no description of randomisation techniques given.
Allocation concealment (selection bias)	Unclear risk	Did not report how allocation was concealed.
Blinding (performance bias and detection bias) All outcomes	High risk	Open‐label study, no attempt at blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	65 participants from 88 randomised achieved primary outcome. A total of 52 participants prematurely withdrawn from trial. 27 participants withdrew from the 28‐day treatment group with the following reasons: loss to follow‐up (n = 1); protocol deviation (n = 4); recurrence/non‐eradication (n = 21); other (n = 1). 25 participants withdrew from the 56‐day treatment group for the following reasons: withdrawn consent (n = 1); loss to follow‐up (n = 2); protocol deviation (n = 2); recurrence/no eradication (n = 19); abnormal audiology test (n = 1).
Selective reporting (reporting bias)	High risk	Study reports there were no major short‐ or long‐term (3 and 27 months) changes in spirometry, but does not record the figures for either of the 2 groups. Also, only summary statements and no numerical data are provided for weight, height or BMI.
Other bias	Unclear risk	Recruited fewer participants than planned; actually randomised 88 participants (primary outcome evaluable in 65) ‐ planned randomisation of 100 participants. Did not randomise 35 participants from the recruited cohort of 123 participants: 31 because of high P aeruginosa antibody levels, one for an adverse event, one where consent was withdrawn, one for a protocol deviation and one 'other' (unspecified) reason. Participants with raised antibody levels were not included because the investigators believed that they were chronically infected with P aeruginosa based on their antibody results. This trial was initially supported by Chiron and later Novartis Pharma, the manufacturer of TIS.

Taccetti 2012.

Study characteristics
Methods	RCT. Parallel design. Duration: 28 days. Multicentre (13 centres) in Italy.
Participants	223 participants with first ever or new P aeruginosa infection. New infection defined as P aeruginosa isolation following bacterial clearance documented by 3 negative cultures within the previous 6 months. Total cohort Age: over 1 year. Sex: 116 male, 107 female. TNS plus ciprofloxacin (n = 118) Sex: 64 males and 54 females. Colistin plus ciprofloxacin (n = 105) Sex: 52 males and 53 females.
Interventions	Intervention group: TNS 300 mg 2 x daily with 2 x daily doses of ciprofloxacin 15 mg/kg/dose, for 28 days. Control group: 2 x daily inhalation of 2 MU colistin with 2 x daily doses of ciprofloxacin 15 mg/kg/dose, for 28 days.
Outcomes	Primary outcome P aeruginosa eradication defined as 3 negative cultures over 6 months. Secondary outcomes Lung function (FEV1) Period of time free of P aeruginosa Isolation of other pathogens including gram‐negative and aspergillus
Notes	Funding source: Italian Cystic Fibrosis Research Foundation (Grant FFC#17/2007) with the contribution of 'Delegazione FFC di Vicenza'.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation sequence generated by statistical software within permuted blocks of size 10, stratified according to age and FEV1.
Allocation concealment (selection bias)	Low risk	Separation of individuals responsible for randomisation and treatment assignment.
Blinding (performance bias and detection bias) All outcomes	High risk	Open‐label trial so no blinding of participants nor researchers.
Incomplete outcome data (attrition bias) All outcomes	Low risk	38 of 223 randomised participants (17%) dropped out of the trial. The biggest reason for dropping out was lack of compliance with follow‐up protocol (11 from Group A and 13 from Group B) and identification of a pulmonary exacerbation during early eradication therapy (4 from Group A and 5 from Group B). Analysis was by intention‐to‐treat.
Selective reporting (reporting bias)	Unclear risk	We have been unable to locate a published protocol for this trial. The details published on the EudraCT database (number 2008‐006502‐42) describe objectives but not outcomes. In the main paper, the methods section does not describe all the trial objectives. Only eradication, time free of P aeruginosa and spirometry are described in the methods section. These outcomes plus the additional outcomes of isolation of other organisms and adverse events are described in the results.
Other bias	Low risk	No evidence of other bias identified.

TORPEDO 2020.

Study characteristics
Methods	RCT. Parallel group. Open‐label trial. Duration: 12‐week treatment period with a follow‐up of at least 15 months. Multicentre (72 CF centres), 70 in the UK and 2 in Italy.
Participants	286 children and adults randomised. Inclusion criteria Diagnosis of CF. Children over the age of 28 days, older children and adults with CF are eligible with no upper age limitation. Competent adults should provide fully informed written consent to participate in the trial. Minors should have proxy consent by the parent or legal guardian and should provide assent where applicable to participate in the trial. The participant should have isolated P aeruginosa and should be either: P aeruginosa‐naïve (i.e. has never previously isolated P aeruginosa) or P aeruginosa‐free (i.e. a minimum of 4 consecutive cough or sputum samples should be P aeruginosa‐free within a 12‐month period). The participant should be able to commence treatment no later than 21 days from the date of a P aeruginosa positive microbiology report. Exclusion criteria P aeruginosa was resistant to one or more of the trial antibiotics. Participants had a contraindication to any of the trial antibiotics. Participants were already receiving P aeruginosa‐suppressive therapy (e.g. an inhaled antibiotic). Participants had received any P aeruginosa eradication therapy within the previous 9 months. Pregnant or breastfeeding. Participants could participate in the TORPEDO‐CF trial once only and could not be randomly assigned within 4 weeks of taking part in another intervention trial. Assessed for eligibility: 1308 children. Randomised: 286 children (137 allocated to IV antibiotics, 149 allocated to oral antibiotics) Baseline characteristics IV antibiotic group Aged 28 days to 23 months, n (%): 42 (31%). Aged 2 to 11 years, n (%): 71 (52%). Aged 12 to 17 years, n (%): 18 (13%). Adults (18 to 64 years), n (%): 6 (4%); Sex, males/females: 63 / 74. P aeruginosa‐naive, n (%): 81 (59%). P aeruginosa‐free, n (%): 93 (63%). FEV1 % predicted (n = 67), mean (SD): 86.6 (15.8) % predicted. FVC % predicted (n = 67), mean (SD): 92.2 (15.5) % predicted. FEF25-75 % predicted (n = 44), mean (SD): 72.7 (26.6) % predicted. BMI z score (paediatric; n = 125) mean (SD): 0.3 (1). BMI adults (n = 6), mean (SD): 24.6 (1.8). Oral antibiotic group Aged 28 days to 23 months, n (%): 28 (19%). Aged 2 to 11 years, n (%): 92 (62%). Aged 12 to 17 years, n (%): 19 (13%). Adults (18 to 64 years), n (%): 9 (6%). Sex, males/females: 67 / 81. P aeruginosa‐naive, n (%): 93 (63%). P aeruginosa‐free, n (%): 55 (37%). FEV1 % predicted (n = 70, mean (SD): 85.7 (16) % predicted. FVC % predicted (n = 70), mean (SD): 95.1 (14.5) % predicted. FEF25-75 % predicted (n = 53), mean (SD): 70.6 (30.3) % predicted. BMI z score (paediatric; n = 131) mean (SD): 0.3 (0.9). BMI adults (n = 9), mean (SD): 23.2 (2.3). There were more children aged 28 days to 23 months randomised to the IV group, but this was not significant. There were no other notable differences in baseline characteristics between groups.
Interventions	IV antibiotic group: 14 days IV ceftazidime 50 mg/kg/dose, to a maximum of 3 g 3 x daily and IV tobramycin 10 mg/kg/day either 1 x daily or in divided doses (maximum 660 mg/day). Oral antibiotic group: 3 months oral ciprofloxacin 2 x daily (ciprofloxacin dose will be 15 to 20 mg/kg/dose 2 x daily for children aged < 5 years and 20 mg/kg/dose 2 x daily (maximum 750 mg 2 x daily) for those aged ≥ 5 years). Both treatment arms received 3 months of nebulised colistin in conjunction with the randomised treatment. Colistin dose as recommended by the UK CF Trust: 1,000,000 units 2 x daily for children aged ≤ 2 years and 2,000,000 units 2 x daily for children aged > 2 years and adults.
Outcomes	Primary outcome Successful eradication of P aeruginosa infection 3 months after allocated treatment has started, remaining infection‐free through to 15 months after the start of allocated treatment. Secondary outcomes Time to reoccurrence of original P aeruginosa infection Re‐infection with a different genotype of P aeruginosa Lung function (FEV1 , FVC, FEF25-75) Oxygen saturation Growth and nutritional status – height, weight and BMI Number of pulmonary exacerbations Admission to hospital Number of days spent as inpatient in hospital over the 3‐month period after allocated treatment has finished, and between 3 months and 15 months after eradication treatment has finished (other than 14 days spent on initial IV treatment). QoL (CFQ) Utility (EQ‐5D) Adverse events Other sputum/cough microbiology (MRSA, B cepacia complex, Aspergillus, candida infection) Cost per patient (from NHS perspective) Incremental cost‐effectiveness ratio (cost per successfully treated patient, cost per QALY) Carer burden (absenteeism from school or work) Participant burden (absenteeism from education or work)
Notes	Funding source: National institute for Health & Care Research Health Technology Assessment Programme. The funder had no role in data collection, data analysis, data interpretation or writing of the manuscript. This trial assesses whether 10 days IV ceftazidime with tobramycin is superior to 3 months oral ciprofloxacin. Both treatment regimens will be in conjunction with 3 months nebulised colistin.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised by the principal investigator or a delegated clinician using a secure web based randomisation system. The system was controlled centrally by the Liverpool Clinical Trials Centre. Randomisation lists were generated by a statistician who had no involvement in the trial in a 1:1 ratio using block randomisation with random variable block length (initial block length of 3, and then random block sizes of 2 and 4). Randomisation was stratified by centre. Details were not disclosed to the investigators.
Allocation concealment (selection bias)	Low risk	Randomisation was carried out via a centrally controlled system. The system was web‐based and ensured allocation concealment. Randomisation lists were generated by a statistician who had no involvement in the trial and details were not disclosed to investigators. After entry of participant details, treatment allocation was displayed on a secure webpage and an email confirmation was sent to the investigator.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Blinding of participants and personnel Open‐label trial, but the outcome was eradication of P aeruginosa and therefore knowledge of the treatment allocation is unlikely to affect the outcome. However, secondary outcomes may be affected by knowledge of allocation. Blinding of outcome assessors This was an open‐label trial and so the outcome assessors were unblinded. It is unclear whether knowledge of the allocation will have affected outcome assessment, particularly with respect to subjective measures such as QoL and treatment burden.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Detailed description of numbers recruited and randomised. Withdrawals and dropouts described with reasons. 286 participants were randomised and 255 included in primary analysis. 272 were included in the safety analysis.
Selective reporting (reporting bias)	Low risk	Transparent reporting of results. The protocol is available and all outcomes listed in the protocol were reported in the paper. There was also a description of protocol deviations.
Other bias	Low risk	No other risk of bias identified.

Treggiari 2011.

Study characteristics
Methods	RCT. Parallel design. Trial duration for each participant is 18 months. Multicentre (57 centres) in the USA. TNS was provided in an open‐label fashion, while oral ciprofloxacin was provided in a double‐blinded fashion.
Participants	304 participants with CF, previously free of P aeruginosa or had not had positive isolates for 2 years or more. Age: 1 to 12 years. Sex: 150 males, 154 females.
Interventions	All participants received eradication therapy with TNS (Novartis Pharmaceutical Corp) for 28 days with or without ciprofloxacin (Bayer Healthcare AG). The main randomised intervention of TNS, with or without oral ciprofloxacin, commenced after this initial 28 days of treatment. Intervention group: cycled therapy. Comparator group: culture‐based therapy. Furthermore, the time from isolation of P aeruginosa to commencing trial therapy was up to 6 months and in this interval, some participants received antimicrobial therapy.
Outcomes	Primary outcomes Time to first exacerbation requiring IV therapy. Proportion of positive cultures in each group. Secondary outcomes Clinical Time to pulmonary exacerbation not requiring IV antibiotic usage or hospitalisation Frequency of pulmonary exacerbations, hospitalizations, and use of concomitant oral, inhaled, and IV antibiotics Anthropometric measures (linear growth, weight gain) Pulmonary function tests including FVC, FEF25%–75%, and FEV1 (participants 4 years of age and older, able to reproducibly perform spirometry) Total hospitalisation days Adverse events Microbiological Changes in antibiotic susceptibility patterns (minimal inhibitory concentrations of 12 antibiotics) Colony morphology Presence of mucoid isolates from baseline to the end of the trial Emergence of intrinsically aminoglycoside and ciprofloxacin‐resistant non‐pseudomonal organisms (e.g. B cepacia, A xylosoxidans and S maltophilia)
Notes	Funding source: Cystic Fibrosis Foundation grant EPIC0K0, National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases grant U01‐HL080310, and National Center for Research Resources grants ULI‐RR025014‐03, 1UL1‐RR025744, 1UL1‐RR025780, UL1‐RR025005, UL1‐RR0024979, UL1RR025747, UL1‐RR025011, 1UL‐RR024975, and M01‐RR02172.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was carried out by permuted blocks, and performed using a computer‐generated sequence.
Allocation concealment (selection bias)	Low risk	Randomisation assignment was available at the sites via an interactive voice response system with e‐mail confirmation of the treatment assignment.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Inhaled tobramycin was provided in an open‐label fashion, while oral ciprofloxacin was provided in a double‐blinded fashion. All trial personnel and participants were blinded to oral therapy assignment but not to cycled or culture‐based treatment allocation. The core trial investigators were blinded to all treatment allocation for the entire study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Only 2 of 306 randomised participants excluded from the analysis (because they did not receive trial treatment).
Selective reporting (reporting bias)	Low risk	Data on all primary and secondary outcomes reported.
Other bias	Low risk	No imbalance in baseline characteristics. Central trial team (not local investigators) blinded.

Valerius 1991.

Study characteristics
Methods	RCT. Parallel design. Duration: 27 months. Single‐centre trial based in Europe.
Participants	26 participants with a recent positive culture who have never received anti‐pseudomonal therapy. Age: 2 to 9 years. Sex: 13 males, 13 females.
Interventions	Treatment group: oral ciprofloxacin (250 to 750 mg) 2 x daily and inhaled colistin (1 MU) for 3 weeks at entry and each time P aeruginosa isolated. Control group: no anti‐pseudomonas chemotherapy.
Outcomes	Time to chronic colonisation with P aeruginosa (defined as the presence of P aeruginosa in monthly routine sputum specimens for 6 consecutive months and/or the development of precipitating serum antibodies against P aeruginosa).
Notes	Monthly sputum samples. Funding source: not stated
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as an RCT without stratification, but the method of generation of allocation sequence was not stated.
Allocation concealment (selection bias)	Unclear risk	Did not report how allocation was concealed.
Blinding (performance bias and detection bias) All outcomes	High risk	Did not use blinding; interventions different.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Analysed on an intention‐to‐treat basis. Reported data on all participants who were randomised. There were no dropouts reported.
Selective reporting (reporting bias)	Low risk	No evidence of selective reporting found.
Other bias	Low risk	No evidence of other bias identified.

Wiesemann 1998.

Study characteristics
Methods	RCT. Double‐blind, placebo‐controlled. Parallel design. Duration: 2 years. Multicentre trial based in Europe.
Participants	22 children with P aeruginosa‐negative throat swabs or sputum cultures for > 1 year and negative serum antibody titres were eligible. Age: 4 to 18 years. Sex: 9 males, 13 females.
Interventions	Treatment group: TNS 80 mg inhaled 2 x daily. Control group: inhaled placebo.
Outcomes	Time to clearance of P aeruginosa from the airway.
Notes	Monthly sputum or oropharyngeal swabs during trial period. Funding source: not stated
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Allocation sequence was generated using a coin flip for pairs of participants. There is no information as to who was responsible for the coin flip or what controls were in place to ensure validity of the result of the coin flip.
Allocation concealment (selection bias)	Unclear risk	Did not report how allocation was concealed.
Blinding (performance bias and detection bias) All outcomes	Low risk	Reported as double‐blind. Participants were blinded by providing a placebo inhalation with a similar taste to the treatment inhalation, but it is not clear whether the clinicians administering the treatment were blinded to treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	2 out of 11 participants withdrew from treatment group; 5 out of 11 participants withdrew from placebo group. The trial was analysed on an available case basis.
Selective reporting (reporting bias)	High risk	Reported there was no change in spirometric pulmonary function during or after the treatment period, but no data were given.
Other bias	Low risk	No evidence of other bias identified.

A xylosoxidans: Achromobacter xylosoxidans
AZLI: aztreonam lysine
B cepacia: Burkholderia cepacia
BAL: bronchoalveolar lavage
BMI: body mass index
CF: cystic fibrosis
CFQ: Cystic Fibrosis Questionnaire
CFTR: cystic fibrosis transmembrane conductive regulator
CRISS: Chronic Respiratory Infection Symptom Score
FEF_25-75: forced expiratory flow between 25% and 75% of vital capacity
FEV₁: forced expiratory volume at one second
FVC: forced vital capacity
IgG: immunoglobulin G
IQR: interquartile range
IRT: immunoreactive trypsinogen
IV: intravenous
MRSA: methicillin‐resistant Staphylococcus aureus
MU: million units
NPD: nasal potential difference
P aeruginosa: Pseudomonas aeruginosa
QALY: quality added life year
QoL: quality of life
RCT: randomised controlled trial
S maltophilia: Stenotrophomonas maltophilia
SAE: serious adverse event
TNS: tobramycin nebuliser solution

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Alothman 2002	Drug tolerability trial, not eradication therapy.
Alothman 2005	Drug tolerability trial, not eradication therapy.
Ballman 1998	Eradication treatment not used. Observational study.
Brett 1992	Participants allocated to treatment by minimisation on the basis of IgG levels and clinical indications compared to therapy based on clinical indications alone.
Bustamante 2014	The control group for this study included participants with chronic colonisation of P aeruginosa.
Church 1997	Symptomatic treatment not eradication.
Clancy 2013	Participants chronically infected with P aeruginosa.
Coates 2011	Participants chronically infected with P aeruginosa.
Di Cicco 2014	This trial concerned rhinosinusitis and not lung infection.
Elborn 2015	Participants chronically infected with P aeruginosa.
Flume 2015a	Participants chronically infected with P aeruginosa.
Flume 2015b	Participants chronically infected with P aeruginosa.
Flume 2016	Participants chronically infected with P aeruginosa.
Frederiksen 1997	Historical control group.
Frost 2021	Symptomatic treatment not eradication.
Geller 2007	Pharmacokinetic and drug tolerability trial, not eradication therapy.
Geller 2011	Participants chronically infected with P aeruginosa.
Gibson 2007	Not randomised and with no allocation concealment.
Goss 2009	Participants chronically infected with P aeruginosa.
Griese 2002	Case‐control study.
Hansen 2015	Symptomatic treatment, not eradication.
Heinzl 2002	No control group.
Herrmann 2017	Symptomatic treatment, not eradication.
Kenny 2009	Retrospective cohort study.
Konstan 2010	Participants chronically infected with P aeruginosa.
Konstan 2011	Participants chronically infected with P aeruginosa.
Konstan 2015	Participants chronically infected with P aeruginosa.
Latzin 2008	The primary aim of this trial was not to evaluate eradication regimens for P aeruginosa and 112 of 118 participants were treated for an acute exacerbation or suppression of chronic infection with P aeruginosa.
Lenoir 2007	Trial not designed to look at eradication of P aeruginosa. At baseline, 47 of 59 participants had chronic infection with P aeruginosa.
Littlewood 1985	No control group.
Mainz 2014	Sinonasal nebulisation of antibiotic aiming to eradicate from the sinuses only.
Mazurek 2012	Participants chronically infected with P aeruginosa.
Oermann 2009	Participants chronically infected with P aeruginosa, not an eradication trial, no randomisation.
Postnikov 2000	No control group and no randomisation.
Postnikov 2007	Not an eradication trial, participants chronically infected with P aeruginosa.
Prayle 2013	Participants chronically infected with P aeruginosa.
Ramsey 1999	Participants chronically infected with P aeruginosa.
Ratjen 2001a	No control group.
Retsch‐Bogart 2008	Participants chronically infected with P aeruginosa.
Retsch‐Bogart 2009	Participants chronically infected with P aeruginosa.
Rietschel 2009	Pharmacokinetic trial of inhaled tobramycin, not eradication therapy.
Ruddy 2013	Pharmacokinetic trial.
Schaad 1997	Symptomatic treatment not eradication.
Schelstraete 2010	No randomisation or eradication therapy.
Schuster 2013	Drug tolerability trial in chronic P aeruginosa infection, not eradication therapy.
Stass 2013	Pharmacokinetic trial.
Steinkamp 1989	No control group.
Steinkamp 2007	Participants chronically infected with P aeruginosa.
Stockmann 2015	Participants with chronic P aeruginosa.
Taccetti 2005	Primary outcome did not have a control group. Historical controls utilised for other outcomes. No randomisation.
Tramper‐Stranders 2009	Trial of prophylaxis against future infection with P aeruginosa, not of eradication.
Trapnell 2012	Participants chronically infected with P aeruginosa.
Vazquez 1993	Historical control group.
Wainwright 2011a	Randomised to therapy directed by the results of bronchoalveolar lavage compared to therapy based on clinical indications or upper respiratory samples.
Wainwright 2011b	Participants chronically infected with P aeruginosa.

P aeruginosa: Pseudomonas aeruginosa

Characteristics of studies awaiting classification [ordered by study ID]

Noah 2010.

Methods	Single‐centre, randomised, prospective trial.
Participants	Stable children with CF and positive surveillance cultures for P aeruginosa.
Interventions	Intervention group: nebulised tobramycin 300 mg 2 x daily for 4 weeks. Control group: IV ceftazidime with tobramycin for 2 weeks at standard weight‐adjusted doses.
Outcomes	Primary outcome Change in BAL fluid percentage neutrophils from the most affected lobe at bronchoscopy Secondary outcome Change in BAL fluid differential cell counts, cytokines and bacterial quantity
Notes	8 participants from a total of 15 had first ever isolate of P aeruginosa and can be included in this review. Outcome data for these 8 participants not published, author contacted for them.

BAL: bronchoalveolar lavage
CF: cystic fibrosis
IV: intravenous 
P aeruginosa: Pseudomonas aeruginosa

Characteristics of ongoing studies [ordered by study ID]

EUCTR2007‐003868‐22‐FR.

Study name	Assessment OG efficacy and tolerability of inhaled tobramycin vs placebo in cystic fibrosis patients receiving antibiotherapy for 28 days for pseudomonas aeruginosa primo colonisation.
Methods	RCT. Double‐blind parallel design. Multicentre trial (25 sites anticipated).
Participants	Children and adults aged > 12 months with CF. Planned number of participants n = 118. First colonisation with P aeruginosa and receiving antibiotic treatment according to consensus conference.
Interventions	Intervention group: inhaled tobramycin (Erempharma®)300 mg/day by aeroneb for 28 days. Control group: inhaled placebo solution given in the same way as the intervention.
Outcomes	Primary outcome P aeruginosa rate in bronchial secretions (eradication or decrease more than 2 log10 considered significant) Secondary outcomes Safety Microbiological impact on S aureus, P aeruginosa bacterial charge during follow‐up
Starting date	2007
Contact information	No details given.
Notes	Sponsor for this study is Laboratoire Erempharma, France (commercial)

EUCTR2011‐006171‐19‐IT.

Study name	Randomised multicentric clinical trial upon efficacy of two different drugs combination to eradication of early P aeruginosa infection in cystic fibrosis patients over 5 years old.
Methods	RCT. Open‐label parallel design. Multicentre trial.
Participants	People with CF over the age of 5 years with early P aeruginosa infection. Regularly seen in CF centres. Without signs of an exacerbation.
Interventions	Duration of the trial is 6 months and compares 2 different antibiotic protocols. Intervention group: 500 mg oral ciprofloxacin and inhaled colistin mesilate sodium (Promixin). Comparator group: 500 mg oral ciprofloxacin and inhaled tobramycin (300 mg/4 mL).
Outcomes	Primary outcome Eradication of early infection Secondary outcomes Evaluation of antibodies FEV1 Growth BMI Additional antibiotic use Number of exacerbations
Starting date	2012
Contact information	Name: Ambulatorio Fibrosi Cistica Address: Viale Pieraccini 24 50039 Firenze Italy Telephone: 0555662474 Email: g.taccetti@meyer.it
Notes	Sponsor of the study is Azienda Ospedaliera Meyer, Italy (non‐commercial)

EUCTR2015‐003881‐96‐IT.

Study name	EUCTR2015‐003881‐96‐IT
Methods	RCT. Open‐label parallel design. Single‐centre trial conducted in Italy.
Participants	51 participants (children aged 2 to 17 years, n = 40; adults, n = 11). Target sample size = 112 participants.
Interventions	Intervention group: classic eradication therapy as per standard of care with nasal lavage with colistin (2 million U twice a day) for a period of 4 weeks. Control group: standard care (participants received their classic eradication therapy as per standard of care).
Outcomes	Eradication of P aeruginosa from the lower airways (defined as 3 negative, successive P aeruginosa cultures within 6 months). Recurrence of P aeruginosa at 6 months. Eradication of P aeruginosa from upper airways (defined as 3 negative, successive P aeruginosa cultures within 6 months). Adverse events
Starting date	Date of first enrolment 17 May 2016
Contact information	Name: Fibrosi Cistica Address: Viale Pieraccini 24 50139 Firenze Italy Telephone: 0555662474 Email: giovanni.taccetti@meyer.it
Notes

BMI: body mass index
CF: cystic fibrosis
FEV₁: forced expiratory volume at 1 second
P aeruginosa: Pseudomonas aeruginosa
RCT: randomised controlled trial
S aureus: Staphylococcus aureus
TNS: tobramycin nebuliser solution

Differences between protocol and review

2023

There were no further changes leading to differences to the protocol.

2014

The inclusion criteria have been changed to include participants who have received study treatment within six months of the first isolation of P aeruginosa (previously not more than two months). This is to reflect differences in clinical practice between Europe and North America and to allow trials from earlier decades (where early treatment of P aeruginosa was not established clinical practice) to be included. A large trial (306 participants), published in 2011, is therefore now eligible for inclusion (Treggiari 2011). However, it is possible that, where infection has been present for as long as six months, it may have become more difficult to eradicate.

In recent years 28 days of inhaled tobramycin has been recommended as 'standard of care' for eradication of P aeruginosa in guidelines (Döring 2012). This has been reflected in trial design, where investigators have designed their trials to ensure that all participants receive an initial 28‐day course of inhaled tobramycin before randomisation to the next stage of therapy. We have therefore altered our eligibility criteria to allow trials where all participants receive some eradication therapy before randomisation (Treggiari 2011).

We have added cost as an outcome measure, as cost‐effectiveness has become increasingly important in CF care. None of the trials included to date have reported this outcome, but future trials may do so.

2009

After the new lead reviewer re‐assessed the review, the section 'Objectives' was expanded to include the sentence:

'To investigate whether there is evidence of superiority or improved cost‐effectiveness between antibiotic strategies.'

Currently, we have included both P aeruginosa‐free and P aeruginosa‐naive individuals according to the definition by Lee (Lee 2003). At the update in 2009 we have added plans to analyse these subgroups separately if sufficient data become available from included studies in the future.

2005

Two clinically relevant additional outcomes were added at review stage to the ones we had originally listed:

1. Time to chronic infection (defined as the presence of P aeruginosa in each monthly sputum sample for six consecutive months or the presence of precipitating antibodies to P aeruginosa or both)

2. Clinical and radiological scores

Contributions of authors

Damian Wood wrote the first draft of the review and both Damian Wood and Alan Smyth edited it to produce the final version of the original review. Both Damian Wood and Alan Smyth worked together on updated versions of the review until 2007.

As from the update in Issue 2, 2009 Damian Wood stepped down and Simon Langton Hewer took over as lead author. Alan Smyth remained as co‐author. Both authors screened references for inclusion and drafted updates of the review.

For the 2023 update, three new additional co‐authors have been added to the team; Sherie Smith, Nicola Rowbotham and Alex Yule. These three authors screened references for inclusion, extracted data and assessed risk of bias. Sherie Smith added the new studies to the review and updated the analyses, text of the review and summary of findings tables. All authors contributed to writing the manuscript.

Simon Langton Hewer acts as guarantor of the review.

Sources of support

Internal sources

• No sources of support provided

External sources

• National Institute for Health Research, UK

  This systematic review was supported by the National Institute for Health & Care Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group.

Declarations of interest

Dr Langton Hewer is the lead investigator on the included trial Torpedo‐CF: Trial of Optimal Therapy for Pseudomonas Eradication in Cystic Fibrosis, a multicentre study funded by the UK National Institute for Health & Care Research and published in Lancet Respiratory Medicine. He has also received speaker fees from Vertex Pharmaceuticals (this company does not manufacture any drugs that might be eligible for consideration in this review).

Dr Nicola J Rowbotham declares no potential conflict of interest.

Mrs Sherie Smith declares no potential conflict of interest.

Dr Alex Yule declares he is currently a clinical research fellow working on the GIFT‐CF3 Study (NCT04618185). This study has received funding from Vertex Pharmaceuticals (who do not manufacture any drugs that might be eligible for consideration in this review).

Prof. Smyth declares he holds a patent for alkyl quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof (not relevant to any intervention included in this review); he also declares holding a research grant from Vertex Pharmaceuticals (company does not produce any relevant medication for this review). Prof. Smyth is joint chief investigator on the published trial 'Torpedo‐CF: Trial of Optimal Therapy for Pseudomonas Eradication in Cystic Fibrosis' which is included in this review.

New search for studies and content updated (conclusions changed)