Elsevier

The Lancet

Volume 365, Issue 9459, 12–18 February 2005, Pages 573-578
The Lancet

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

https://doi.org/10.1016/S0140-6736(05)17906-9Get rights and content

Summary

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 (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 No patients developed hearing loss during the study, although two reported acute dizziness and were withdrawn from the study.

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.

Introduction

Aminoglycoside antibiotics are widely used for the management of pulmonary exacerbations in patients with cystic fibrosis who have chronic pulmonary infection with Pseudomonas aeruginosa.1 Patients with the disease might receive repeated and extended courses of treatment with aminoglycosides, often from a young age, which makes them especially vulnerable to the adverse effects of these drugs, mainly nephrotoxicity and ototoxicity. In the kidney, standard doses of aminoglycosides can cause proximal tubular damage, whereas toxic concentrations cause acute tubular necrosis.2 In the inner ear, these drugs can damage cochlear hair cells, leading to sensorineural deafness.3

Aminoglycosides are generally given three-times daily. However, a regimen of one dose per day might be more effective because it makes use of concentration-dependent killing (bacterial killing dependent on the highest concentration of tobramycin achieved) and the post-antibiotic effect (bacterial killing continuing even when tobramycin concentrations are no longer measurable).2 Once daily treatment also minimises adaptive resistance.4 Once daily dosing might also be less nephrotoxic than the three-times daily regimen because a high serum concentration could saturate uptake of aminoglycosides in the proximal tubule.2 This treatment would also substantially reduce the burden of care for families.

The pharmacokinetics of aminoglycosides in patients with cystic fibrosis are different from that in non-cystic-fibrosis individuals (increased volume of distribution and rapid elimination).5 In other groups of individuals, investigators have not considered specific outcome measures (improvement in symptoms and lung function) that are relevant to cystic fibrosis, and so the data cannot be extrapolated to these patients. A systematic review6 of studies of single versus multiple daily dosing of aminoglycosides in cystic fibrosis identified only three studies relating to 175 affected patients. These studies had insufficient power to detect a difference between regimens.

Therefore, we designed a large, double-blind, randomised controlled trial to compare the safety and efficacy of once versus thrice daily aminoglycosides for pulmonary exacerbations of cystic fibrosis.

Section snippets

Patients

All participants had a diagnosis of cystic fibrosis (ie, sweat chloride >60 mmol/L or a genotype known to cause the disease). Patients were eligible if aged over 5 years and able to participate in pulmonary-function tests reliably. P aeruginosa had to have been isolated from respiratory secretions on at least one occasion, with the most recently isolated organism showing sensitivity to tobramycin, ceftazidime, or both. Bacterial culture of respiratory samples was done at patients' local

Results

Figure 1 shows the trial profile. Enrolment took place between February, 1999, and April, 2003. Of 219 patients completing the study, 125 were assigned a paediatric randomisation code and 94 an adult code. However, six patients seen in paediatric clinics were assigned an adult code because bodyweight was greater than 40 kg, and five seen in adult clinics were assigned a paediatric code (bodyweight <40 kg). Results of analysis are presented by initial classification to preserve stratification,

Discussion

We have shown that once daily tobramycin (with ceftazidime) has equivalent efficacy to conventional three-times daily treatment for pulmonary exacerbations of cystic fibrosis. In children, we noted a difference in percentage change in serum creatinine concentrations that was in favour of once daily tobramycin and significant in the per-protocol group. This group had a full course of treatment and was therefore at greatest risk of toxic effects. A smaller rise in the proximal tubular enzyme NAG

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