Dosage adjustment and clinical outcomes of long-term use of high-dose tobramycin in adult cystic fibrosis patients

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Abstract
A two-phase study was undertaken designed to investigate the impact of computer-aided drug monitoring on tobramycin concentrations and clinical outcomes in adult patients with cystic fibrosis. In phase one, a baseline (historical control) study of drug use patterns was performed. During the second phase, patients admitted for intravenous treatment with tobramycin for acute exacerbations of pseudomonal pulmonary infections were randomly allocated to one of two schedules. Group A patients had tobramycin dosage regimens decided by clinicians based on pre-existing protocols using serum tobramycin assay data determined three times weekly. Group B patients had dosage regimens determined by a computerized pharmacokinetic predictive program using both population-based pharmacokinetic parameter estimation and fitting of serum concentration-time data using Bayesian regression. The agreed therapeutic target was a peak serum tobramycin concentration of 8–10 mg/L and a trough concentration of 1–2 mg/L. There was a major difference between the two groups comparing the number of paired trough and peak concentrations within the target concentration ranges (group A–14%; group B–34·7%, χ2 test, P < 0001). Average peak tobramycin level was higher in group A patients (A = 8·2±2·2 mg/L; B = 7·5± 1·9 mg/L; P < 0·005) while average trough level was higher in group B patients (A = 0·78±0·44 mg/L; B = 1·01±0·42 mg/L; P < 0·05). Average dosage was higher in group B patients (A = 8·56±2·36 mg/kg/day; B = 9·56±1·83 mg/kg/day; P < 0·05) and average dosing interval was shorter in group B patients (A = 8·05±1·01 h: B = 6·57±0·82 h; P < 0·05). No difference in clinical outcome or mortality was observed and mean hospital stay was not different between the two groups. No case of aminoglycoside-induced nephrotoxicity or ototoxicity was observed. We conclude that the use of a computerized predictive programme can improve the control of aminoglycoside concentration-time profiles and allow targeted dosing without toxicity. The system allows for the possibility of tailoring dosage regimens aimed at optimizing efficacy and quality of life with minimal toxicity.

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