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.
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.
| Original language | English |
|---|---|
| Article number | CD004197 |
| Number of pages | 135 |
| Journal | Cochrane Database of Systematic Reviews |
| Volume | 2023 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 02 Jun 2023 |
| Externally published | Yes |
Bibliographical note
Funding Information:This project was supported by the National Institute for Health & Care Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.
Funding Information:
1. Time to P aeruginosa recurrence after the first quarter of therapy. 2. Safety (as measured by adverse events, electrocardiogram, and audiologic monitoring). 3. Frequency of exacerbations. 4. Frequency of P aeruginosa-positive cultures. 5. Rates of antibiotic use. 6. Hospitalisations. 7. Change in nutritional status (height, weight). 8. Lung function (in participants over 4 years of age). 9. Patient/parent-reported respiratory symptoms (using CRISS) 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.
Funding Information:
Funding source: Italian Cystic Fibrosis Research Foundation (Grant FFC#17/2007) with the contribution of 'Delegazione FFC di Vicenza'.
Funding Information:
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 aHer 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).
Publisher Copyright:
Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ASJC Scopus subject areas
- Pharmacology (medical)