Ciprofloxacin dry powder inhaler in cystic fibrosis.

Correspondence to Professor J Stuart Elborn; [email protected] Inhaled antibiotics are the backbone of care for people with cystic fibrosis (CF) who have lung infection due to Pseudomonas aeruginosa. They have significantly contributed to the improved quality of life (QOL) and increased survival in people with this disease. The systematic application of antibiotic eradication therapy for new or recurrent infections with P. aeruginosa and for long-term use of inhaled antibiotics in people with CF is now standard of care. There are currently two inhaled antibiotics licensed in the USA (tobramycin and aztreonam lysine) and four in Europe (tobramycin, aztreonam lysine, colistimethate sodium and levofloxacin). One of the current challenges of using inhaled antibiotics in CF is that tobramycin is licensed for use on alternate months, though clinical practice assessed from registries suggests that the majority of physicians when using tobramycin suggest a second antibiotic for the alternating months. Tobramycin inhalation by inhalation solution or dry powder has been available for 15 years and colistimethate sodium dry powder and has recently been licensed by the European Medicines Agency (EMA). 7 Tobramycin given on alternate months improved forced expiratory volume in 1 s (FEV1) and reduced pulmonary exacerbations compared to placebo. Colistimethate sodium has only been tested in a head-to-head active comparator study against tobramycin and demonstrated non-inferiority in patients. It has not been studied in a large placebo-controlled trial. Levofloxacin as an inhalation solution, though approved for over 18-year-olds in Europe, is not yet available to clinicians for use. This fluoroquinilone demonstrated good activity against P. aeruginosa and improvement in FEV1 compared to placebo in a phase II study. In a non-inferiority, phase III active comparator trial against nebulised tobramycin there was no difference in FEV1 changes and a small advantage in favour of levofloxacin for time to next antibiotics. A longer phase II study, as yet unpublished, showed a small advantage in FEV1 (3–4%) for levofloxacin compared to placebo and no difference in frequency of pulmonary exacerbations. The addition of further inhaled antibiotics is likely to make a valuable contribution to management of people with CF and so it is disappointing to see a negative study of dry powder inhaled ciprofloxacin in this study published in BMJ Open Respiratory Research. This was a well-designed and powered, dose finding study in people with CF using a welldesigned dry powder device, with between 90 and 100 patients in each of the two dose groups and a placebo comparator. The study failed to meet its primary end point of change in FEV1 from baseline to the end of inhaled treatment at 29 days. There was a modest antimicrobial effect with a reduction of around 1.5 log CFU/g at day 14 though this was not sustained to day 29 where the difference was not significant compared to placebo. There was a trend in improvement in QOL scores and there were no major safety concerns. There are a number of reasons why the ciprofloxacin may have been ineffective in this clinical trial. First, the authors suggest, this was a cohort of patients with relatively advanced disease. This, however is very similar to the cohort described in phase III levofloxacin, placebo-controlled trial where there also was only a small change in FEV1 of around 4% predicted. In the ciprofloxacin study the difference compared to placebo is also in this range at 1–2% predicted. The changes in the sputum density of P. aeruginosa were also similar for levofloxacin and, ciprofloxacin. Ciprofloxacin, in common with other fluoroquinolones, rapidly induces resistance and the microbiology data suggests that the antimicrobial effect of dry powder inhaled ciprofloxacin was attenuated after 30 days. This may have been due to the induction of resistance and contributed to the lack of improvement in FEV1. However, other recent studies changes in FEV1 do directly relate to changes in microbial load. It is also possible that the