Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis - the TOPIC study: a randomised controlled trial

Background Intravenous tobramycin (three-times daily) is widely used for pulmonary exacerbations in, patients with cystic fibrosis who have chronic Pseudomonas aeruginosa infection. We undertook a double-blind, randomised controlled trial to assess the safety and efficacy of once versus three-times daily tobramycin in these patients. Methods 244 patients from 21 cystic-fibrosis centres in the UK were randomly, assigned to once or three-times daily tobramycin (with ceftazidime) for 14 days. Treatment was given as 30-min infusions of. tobramycin in 0.9% saline. Primary outcome measure was change in forced expiratory volume in 1 s (FEV1), over the 14 days of treatment, expressed as a percentage of the predicted normal value for age, sex, and height. We also measured the change in FEV1 expressed as a percentage of baseline. Secondary outcomes included change in serum creatinine. The study was powered for equivalence, and primary analysis was per protocol. Findings 219 patients (107 once daily, 112 three-times daily) completed the study per protocol. None was lost to follow-up, although 20 discontinued,intervention. Of 122 patients assigned to once daily treatment, three did not receive the study regimen. The mean change in FEV1 (% predicted) over 14 days was similar on the two regimens (10.4% [once daily] vs 10.0% [three-times daily]; adjusted mean difference 0.4% [95% CI -3.3 to 4.1]). Mean % change in FEV1 from baseline was also similar in both treatments (21.9% vs 22.1%; -0.1% [-8.0 to 7.9]). There was no significant difference in % change in creatinine from baseline (-1.5% [once daily] vs 1.7% [three-times daily]). However, in children, once daily treatment was significantly less nephrotoxic than was thrice daily (me an % Change in creatine -4.5% [once daily] vs 3.7% [thrice daily]; adjusted mean difference -8.0%, 95% Cl -15.7 to -0.4). No patients developed hearing loss during the study, although two reported acute dizziness and were withdrawn from the study. Interpretation Intravenous tobramycin has equal efficacy if given once or three-times daily (with ceftazidime) for pulmonary exacerbations of cystic fibrosis. The once daily regimen might be less nephrotoxic in children.