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Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial

Author(s): Langton Hewer SC, Smyth AR, Brown M, on behalf of the TORPEDO-CF study group.

Lancet Respir Med 2020; 8: 975–86

Respiratory infections
Epidemiology
General respiratory patient care
Public health

Digest Author(s): Sarah Cullivan, MD / 24 October, 2020

Chronic pulmonary infection with Pseudomonas aeruginosa is associated with accelerated lung function decline, increased hospitalisations and increased morbidity and mortality in cystic fibrosis (CF). While it is generally accepted that antibiotic eradication of pseudomonas is effective, the optimum treatment regimen is unknown and current guidelines are inconsistent. This prospective, multicentre randomised controlled trial compared intravenous (IV) ceftazidime and tobramycin for 14 days, to oral ciprofloxacin for 12 weeks, to determine which regimen was superior in achieving and maintaining P aeruginosa eradication. Both study arms received concomitant inhaled colistimethate sodium for 12 weeks at treatment initiation.

Inclusion required a recent isolate of P aeruginosa, in patients who were pseudomonas naïve or pseudomonas infection free for ≥1 year. Randomisation was performed using web-based software and blinding was deemed impractical due to the nature of the interventions. The primary endpoint was pseudomonas eradication from respiratory samples at 3 months and 15 months from treatment allocation, and results were analysed using the intention to treat principle. Secondary endpoints included time to recurrence of original pseudomonas strain, re-infection with an alternative genotype or other respiratory organisms. Data regarding peripheral oxygen saturations, BMI, pulmonary exacerbations, hospital admission and duration, pulmonary function tests, and quality of life (CFQ-R20 and EQ-5D-3L21) were also collected and an economic analysis was performed.

Children (older than 28 days old) and adults with confirmed CF, were prospectively enrolled in 72 CF centres in 2 countries (70 UK, 2 Italy) between Oct 2010 and Jan 2017. 286 patients were randomly assigned IV (n=137) and oral (n=149) therapy. 30 subjects were excluded from the primary analysis as the 15 month microbiological sample were not available. In the remaining subjects, there was no significant difference in the primary outcome, as 44% (55 of 125) in the IV cohort and 52% (68 of 130) in the oral treatment group achieved the primary outcome (RR 0·84, 95% CI 0·65 to 1·09; p=0·18). Regarding secondary endpoints, an effect of treatment was noted on lung function and BMI, with significant higher FVC (p=0·04) and lower BMI (p=0·029) noted in subjects in the IV treatment arm, though potential confounders were highlighted. Significantly fewer subjects in the IV cohort were hospitalised in the 12 months following eradication therapy (RR 0·69, 95% CI 0·50 to 0·95; p=0·020). There were no statistically significantly differences across any other secondary endpoints, including patient questionnaires. Adverse events were similar between groups and an economic analysis revealed cost savings of £5939 per patient with oral therapy when compared to IV. The authors conclude that there is no advantage to IV treatment as a first-line eradication choice.

Comments:

  • This study adds valuable information in an area where high quality RCT data was lacking and will no doubt have meaningful implications for clinical practice and associated guidelines. The pragmatic design and large sample size should be commended, though caution is advised when translating these results to an adult population as only 5% of the study population were adults.
  • The specific reason for significantly fewer hospital admissions in the IV group is unclear and while the authors postulate that this may reflect individual choice to decline additional admissions, this finding requires further exploration.
  • This study also highlights that even in the controlled environment of a RCT, suboptimal eradication rates were achieved in both groups, as approximately 50% of all patients were pseudomonas free at 15 months. Early detection of pseudomonas infection and optimisation of eradication strategies are priorities for future studies.