Pseudomonas eradication in cystic fibrosis: who will join the ELITE?
- Correspondence to Dr Alan R Smyth, Associate Professor & Reader in Child Health, Division of Child Health, & Nottingham Respiratory Biomedical Research Unit, E Floor, East Block, Queens Medical Centre, Nottingham NG7 2UH UK;
Arguably, the most significant event in the life of a person with cystic fibrosis (CF) is the acquisition of chronic pulmonary infection with Pseudomonas aeruginosa. It heralds, in many cases, more hospitalisations,1 a more rapid decline in pulmonary function and a shorter life expectancy.2 P aeruginosa has the ability to form biofilms which are composed of non-motile organisms embedded in an exopolysaccharide matrix and which confer resistance to antibiotics.3 In individuals with CF, biofilms have been observed in lungs examined at autopsy and explanted lungs from transplant recipients.4 The extraordinary persistence of infection with P aeruginosa in the CF lung is thought to derive from biofilm formation. The mucoid phenotype of P aeruginosa is a marker of biofilm formation,4 and this phenotype is in turn associated with a worse prognosis compared with non-mucoid organisms.5 However, in the initial stages of infection when the organism is mainly in planktonic form, there is an opportunity to eradicate the infection before it becomes persistent.
The first randomised controlled trial of an eradication regimen for early P aeruginosa infection was reported by Valerius and Koch in 1991.6 This evaluated a 3-week regimen of nebulised colistin and oral ciprofloxacin (compared with no treatment) and found that fewer patients developed chronic infection in the active group over a period of 2 years. A further study using historical controls suggested that a longer course of colistin and ciprofloxacin (3 months) achieved a longer period free of recurrent infection with P aeruginosa.7 Nebulised tobramycin has been compared with placebo in two randomised controlled trials which have shown successful short-term eradication of P aeruginosa from bronchoalveolar lavage specimens8 and from throat or sputum cultures.9 A comparison of nebulised colistin plus ciprofloxacin with nebulised tobramycin was underpowered and showed no difference between groups.10 Indeed, there have been few studies which have compared alternative regimens or durations of treatment. The ELITE study11 by Ratjen et al reported in this issue of Thorax is therefore a welcome addition to the evidence base for eradication treatment (see page 286).
ELITE incorporates an innovative study design whereby patients who were free of P aeruginosa for at least a year received eradication treatment with nebulised tobramycin for 28 days. At the time of enrolment, serum samples were taken for analysis for antibodies to Pseudomonas exoenzymes. These results were available by the end of the initial 28 days of treatment, and those patients who were antibody positive (suggesting chronic infection) were excluded from randomisation. Antibody-negative patients were randomised to either stop eradication therapy or to have a further 28 days of treatment. The primary outcome (time to recurrence of infection with P aeruginosa) was approximately 26 months in both groups. Secondary outcomes—including the proportion of patients in whom P aeruginosa was eradicated initially, spirometry and nutritional indices—showed no significant differences between groups. Reported adverse effects and measures of renal function and hearing did not differ between groups. The primary outcome was evaluable in 65 patients, less than the estimated sample size of 100 patients randomised. A shorter course of eradication therapy offers clear advantages for the CF team, the patients and their families. However, the investigators' conclusion that there is no difference between the 28-day and 56-day regimens would be more robust if they had employed an equivalence study design.12
So, where next for Pseudomonas eradication? Eradication therapy with either a colistin/ciprofloxacin regimen or with nebulised tobramycin is recommended standard care in European CF centres.13 A Cochrane review concluded that eradication is achieved, at least initially, but does not recommend one regimen over another.14 The ELITE study has provided the first randomised comparison of eradication regimens of different durations. Studies of eradication regimens comparing different drugs or different approaches to drug administration are badly needed. A number of important studies are ongoing or are due to report their findings in the near future.
The recently completed EPIC study has randomised over 300 children with newly acquired Pseudomonas infection to either culture-directed therapy or quarterly cycles of inhaled tobramycin (28 days of tobramycin followed by 56 days off treatment) for 18 months. Patients in each group were further randomised to receive 14 days of either ciprofloxacin or placebo orally—again either directed by culture or in quarterly cycles.15 The results of the trial will be published within the next year. The Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study16 takes the concept of culture-directed therapy a stage further by randomising children to receive either a single bronchoalveolar lavage (BAL) at 5 years of age, or BAL at baseline, a further BAL specimen to confirm any upper respiratory isolates of P aeruginosa, BAL with intravenous antibiotics and a final specimen at 5 years of age. In both groups a robust eradication regimen (2 weeks intravenous antibiotics, 4 weeks ciprofloxacin and 8 weeks nebulised tobramycin) is given where isolates are positive for P aeruginosa. Again, the results are expected within a year. In contrast, the TORPEDO study (http://www.controlled-trials.com/ISRCTN02734162/TORPEDO-CF), which will commence shortly in the UK, will compare 2 weeks of intravenous antibiotics with 3 months of oral ciprofloxacin, both combined with 3 months of nebulised colistin.
It has been a major achievement of the last two decades of CF care to make eradication treatment for P aeruginosa routine. Eradication, along with meticulous microbiological surveillance and measures to prevent cross-infection, has reduced the median prevalence of chronic Pseudomonas infection to around 11% in children with CF attending UK centres.17 The ELITE study is the first step in determining the optimal eradication regimen. Optimal therapy will be of the shortest duration compatible with long-term eradication, will minimise drug side effects and antibiotic resistance, but with the least possible upset to schooling, work and family life. Getting there will require every CF centre to participate in multicentre trials and the timely application of evidence to clinical practice. Who will join the ELITE?
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Competing interests ARS is Director of the Trent Local Children's Research Network, part of the UK NIHR Medicines for Children Network.
Provenance and peer review Commissioned; not externally peer reviewed.