Combined Dry Powder Tobramycin and Nebulized Colistin Inhalation in CF Patients (CotoCFII)

To assess whether the inhalative combination of Tobramycin/Colistin is more effective in reducing Pseudomonas colony forming units (CFUs) and improvement of lung function than Colistin in mono-therapy.

Cystic fibrosis (CF), the most common autosomal recessive disorder in Western countries, is caused by mutations of the cystic fibrosis transmembrane conductance regulator molecule (CFTR) and affects approximately 40.000 patients in Europe. The majority of CF patients develop chronic pulmonary infections with Pseudomonas aeruginosa. These are normally treated with single antibiotics, administered orally, intravenously or inhalatively. Once the infection becomes chronic, eradication of the pathogen is not any more possible due to biofilm formation of the pathogen and increasing resistance. However, inhalative antibiotic combination therapy might be more efficient than single antibiotic therapy in chronically infected CF patients. This notion is supported by previous in vitro and animal studies using Tobramycin/Colistin combination therapy. Importantly, a pilot study in five CF patients who inhaled consecutively Colistin and Tobramycin solutions for 4 week, revealed a decrease of log10 2.52 ± 2.5 cfu of P. aeruginosa in sputum specimens during the course of the treatment compared to baseline values (p=0.027). The treatment was shown to be safe and well tolerated. However, forced expiratory volume in 1 sec (FEV1) did not differ significantly. Taking advantage of the new development of dry powder inhalation (DPI) antibiotics, specifically TOBI© Podhaler, a larger randomised trial has been performed in which the combined TOBI© Podhaler and Colistin treatment is compared to the monotherapy with Colistin.

TOBI®Podhaler 2 x 112 mg daily for 2 x 28 days (on/off); and Colistin solution 2 x daily 1 Mega continuously for 112 days

The primary endpoint will be the difference of P. aeruginosa cfu/ml in sputum with combined therapy with Tobramycin/Colistin compared to colistin mono-therapy. The analysis will be adjusted for baseline values of each cycle and parametric (paired t-Test) or non-parametric (sign test) methods will be used as appropriate.

Course of FVC relative (percent of expected amount for given body height and gender) during the study

Course of FEV1 relative (percent of expected amount for given body height and gender) during the study

Course of MEF25-75 relative (percent of expected amount for given body height and gender) during the study

Inclusion Criteria: Cystic Fibrosis is verified; Patient is 12 years or older; FEV1 is higher than 25% and lower than 100%; The patients' lung is colonised with P. aeruginosa chronically (≥6 months); P. aeruginosa must be sensitive for Tobramycin or Colistin; Pretreated with Colistin >2 months; Last i.v. antibiotic treatment ≥2 weeks; Informed consent is given by patients/legal representatives Exclusion Criteria: Clinical deterioration is present (exacerbation symptoms); Last Tobramycin inhalation treatment ≤ 2 weeks; Renal dysfunction (creatinine <1.5 fold of normal, glomerular filtration rate (GFR) <80%) at baseline auditoria or vestibular dysfunction, hearing loss Intolerances against Tobramycin, Colistin or Polymyxin B Myasthenia gravis Porphyria Pregnancy and nursing