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