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

SummaryBackgroundIntravenous 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.Methods244 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.Findings219 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 (mean % change in creatine –4·5% [once daily] vs 3·7% [thrice daily]; adjusted mean difference –8·0%, 95% CI –15·7 to –0·4). No patients developed hearing loss during the study, although two reported acute dizziness and were withdrawn from the study.InterpretationIntravenous tobramycin has equal efficacy if given once or three-times daily (with ceftazidime) for pulmonary exacerbations of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.