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Editor,—The paper by Vic and colleagues1 provides useful pharmacokinetic data on the use of once daily aminoglycoside treatment in children with cystic fibrosis. However, their conclusions regarding efficacy and safety must be viewed with caution. They did not perform a power calculation and therefore they cannot exclude the possibility of a type 2 error—that is, one regimen may be more effective but insufficient patients have been studied to demonstrate this. In an equivalence study conventional tests of significance are inappropriate and the results should be expressed as a confidence interval wherein the true difference may lie.2
This study is also too small to make any meaningful comments about toxicity. Ototoxicity appears to be an uncommon complication, and a study of 22 patients will not establish its prevalence with either regimen. Children with cystic fibrosis differ from most other patient groups in that they may receive multiple courses of aminoglycosides and the effects of cumulative toxicity must be measured in any evaluation of once daily treatment. Children with cystic fibrosis who have received large cumulative doses of aminoglycosides have been found to have hearing impairment when sensitive tests such as acoustic emissions have been used.3 Vic et al have studied nephrotoxicity by measuring lysozyme and β2microglubulin in urine. However, they have not looked for clinically important manifestations of renal tubular toxicity such as hypomagnesaemia, which are known to occur with cumulative dosages of aminoglycosides.4
Unfortunately, this study does not provide the information needed to bring about a change in practice, allowing the routine use of a once daily regimen in children with cystic fibrosis. There is urgent need for a large, adequately powered study of oncev three times daily aminoglycosides for pulmonary exacerbations in adults and children with cystic fibrosis.
Dr Vic and colleagues comment:
Our goal was not to show that a once daily regimen was safer and more effective than the conventional regimen, but to study its safety and efficacy on a short term basis. Obviously, a larger number of patients would have enhanced the power of our study and we welcome the suggestion of a larger study comparing once and three times daily tobramycin. We are now able to give some more information on ototoxicity and nephrotoxicity after a three to four year follow up of our patients. Audiometry and assessment of kidney function (serum creatinine, creatinine clearance, 24 hour proteinuria with electrophoresis, lysozymuria, β2 microglobulinura, and urinary N-acetyl-β-D-glucosaminidase activity) was performed in 16 of the 30 cystic fibrosis patients who had taken part in our two studies of once daily amikacin and tobramycin.1-1 1-2 Median age was 12 years (range 8–27 years) and the mean number of antibiotic courses with once daily aminoglycosides was 8 (range 2–15). No cochlear or renal abnormalities were found in these patients, suggesting the absence of cumulative toxicity. Even if these preliminary results strongly suggest that the use of once daily aminoglycosides is safe on a long term basis, we recommend that cochlear and renal function must be examined at least every year in cystic fibrosis patients receiving repeated antibiotic courses with once or thrice daily aminoglycosides.
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