Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis
Abstract
Background
Respiratory tract infection with Pseudomonas aeruginosa occurs in most people with cystic fibrosis. Once chronic infection is established, Pseudomonas aeruginosa is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate.
This is an update of a Cochrane review first published in 2003, and previously updated in 2006 and 2009.
Objectives
To determine whether antibiotic treatment of early Pseudomonas aeruginosa infection in children and adults with cystic fibrosis eradicates the organism, delays the onset of chronic infection, and results in clinical improvement. To evaluate whether there is evidence that a particular antibiotic strategy is superior to or more cost‐effective than other strategies and to compare the adverse effects of different antibiotic strategies (including respiratory infection with other micro‐organisms).
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 abstract books of conference proceedings.
Most recent search: 08 September 2014.
Selection criteria
We included randomised controlled trials of people with cystic fibrosis, in whom Pseudomonas aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous antibiotics with placebo, usual treatment or other combinations of inhaled, oral or intravenous antibiotics. We excluded non‐randomised trials, cross‐over trials, and those utilising historical controls.
Data collection and analysis
Both authors independently selected trials, assessed risk of bias and extracted data.
Main results
The search identified 49 trials; seven trials (744 participants) with a duration between 28 days and 27 months were eligible for inclusion. Three of the trials are over 10 years old and their results may be less applicable today given the changes in standard treatment. Some of the trials had low numbers of participants and most had relatively short follow‐up periods; however, there was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment given the interventions and comparators used. Two trials were supported by the manufacturers of the antibiotic used.
Evidence from two trials (38 participants) at the two‐month time‐point showed treatment of early Pseudomonas aeruginosa infection with inhaled tobramycin results in microbiological eradication of the organism from respiratory secretions more often than placebo, odds ratio 0.15 (95% confidence interval 0.03 to 0.65) and data from one of these trials, with longer follow up, suggested that this effect may persist for up to 12 months.
One randomised controlled trial (26 participants) compared oral ciprofloxacin and nebulised colistin versus usual treatment. Results after two years suggested treatment of early infection results in microbiological eradication of Pseudomonas aeruginosa more often than no anti‐pseudomonal treatment, odds ratio 0.12 (95% confidence interval 0.02 to 0.79).
One trial comparing 28 days to 56 days treatment with nebulised tobramycin solution for inhalation in 88 participants showed that both treatments were effective and well‐tolerated, with no notable additional improvement with longer over shorter duration of therapy. However, this trial was not powered to detect non‐inferiority or equivalence .
A trial of oral ciprofloxacin with inhaled colistin versus nebulised tobramycin solution for inhalation alone (223 participants) failed to show a difference between the two strategies, although it was underpowered to show this. A further trial of inhaled colistin with oral ciprofloxacin versus nebulised tobramycin solution for inhalation with oral ciprofloxacin also showed no superiority of the former, with increased isolation of Stenotrophomonas maltophilia in both groups.
A recent, large trial in 306 children aged between one and 12 years compared cycled nebulised tobramycin solution for inhalation to culture‐based therapy and also ciprofloxacin to placebo. The primary analysis showed no difference in time to pulmonary exacerbation or proportion of Pseudomonas aeruginosa positive cultures. An analysis performed in this review (not adjusted for age) showed fewer participants in the cycled therapy group with one or more isolates of Pseudomonas aeruginosa, odds ratio 0.51 (95% CI 0.31 to 0.28).
Authors' conclusions
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 the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials of two active treatments have failed to show differences in rates of eradication of Pseudomonas aeruginosa. There have been no published randomised controlled trials that investigate the efficacy of intravenous antibiotics to eradicate Pseudomonas aeruginosa in cystic fibrosis. Overall, there is still insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in cystic fibrosis.
PICOs
Plain language summary
Different ways of giving antibiotics to eradicate Pseudomonas aeruginosa infection in people with cystic fibrosis
Review question
We reviewed the evidence for the effectiveness of antibiotics in getting rid of a lung infection with a germ called Pseudomonas aeruginosa in people with cystic fibrosis.
Background
Cystic fibrosis is an inherited condition where the airways often become blocked with mucus. It is associated with chest infections, which can lead to progressive breathing failure and death. A germ called Pseudomonas aeruginosa is a frequent cause of infection and is difficult to treat effectively, once infection has become established.
Search date
The evidence is current to September 2014.
Study characteristics
We wanted to compare different combinations of inhaled, oral and intravenous (IV) antibiotics for eliminating Pseudomonas aeruginosa in people with cystic fibrosis and find out if any single treatment works best and is more cost‐effective. We included seven trials with a total of 744 individuals, but the treatments were mostly different so we could not combine the results. Two trials compared tobramycin to placebo (a dummy treatment). Three trials used a combination of oral ciprofloxacin and inhaled colistin in one group of volunteers and compared this combination to no treatment in one trial, to inhaled tobramycin in a second trial and to oral ciprofloxacin with inhaled tobramycin in the third trial. Another trial compared 28 days of inhaled tobramycin to 56 days of inhaled tobramycin and the final included trial compared regular cycles of inhaled tobramycin (plus oral ciprofloxacin or placebo) to culture‐based inhaled tobramycin (plus oral ciprofloxacin or placebo). Trials included people with cystic fibrosis of both sexes, any age and both mild and more severe lung disease. The trials lasted from 28 days to 27 months.
Key results
Two small trials (38 volunteers) treating early infection showed that, after two months, nebulised antibiotics were better than no treatment and eliminated Pseudomonas aeruginosa in most people. One of these trials reported results over a longer period and these suggested that this effect may last for up to 12 months. Another small trial (26 volunteers) which lasted two years showed that treating early infection with a combination of nebulised and oral antibiotics was better than no treatment at eliminating Pseudomonas aeruginosa. A further trial (88 volunteers), which compared 28 days of nebulised tobramycin solution for inhalation to 56 days, showed both were equally tolerated and effective at eliminating Pseudomonas aeruginosa. Four direct comparisons of oral or inhaled antibiotics (or combinations of both), one of which reported on 223 volunteers, did not find a difference between different antibiotic combinations. A recent, large trial in 306 children (aged up to 12 years) compared a regular cycle of treatment to treatment only when it was shown that a child was infected with Pseudomonas aeruginosa, the treatment used was either an antibiotic or a placebo. When we analysed the data for this review, we found that when children were given a regular cycle of inhaled tobramycin (with either oral ciprofloxacin or placebo) fewer of them grew Pseudomonas aeruginosa from their sputum. The official published results from this trial made an adjustment for age and did not show any difference in the number of times Pseudomonas aeruginosa was grown from samples between the groups, nor was there any difference in the length of time until the patients had their next chest infection.
Quality of the evidence
Some of the trials were conducted between 10 and 20 years ago and the results may not be applicable to patients today. Some trials were small and all the trials had quite a short follow‐up period. Therefore, we could not show whether treatment made people with cystic fibrosis feel better or live longer. Given the types of treatment used in most of the trials, it would have been easy for the volunteers to guess which treatment they were receiving, which might have influenced some of the results. Two trials were supported by the pharmaceutical industry. Further research is still needed to see whether eliminating the bacteria completely improves the well‐being and quality of life in people with cystic fibrosis and to establish which antibiotic combination provides the best way of eliminating Pseudomonas aeruginosa.
