JAC Advance Access originally published online on August 2, 2006
Journal of Antimicrobial Chemotherapy 2006 58(4):822-829; doi:10.1093/jac/dkl328
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Once-daily tobramycin in cystic fibrosis: better for clinical outcome than thrice-daily tobramycin but more resistance development?
1 Department of Pulmonary Medicine, Medical School Hannover Hannover, Germany 2 Department of Pharmaceutics, College of Pharmacy, University of Florida Gainesville, USA
Received 10 November 2005; returned 11 May 2006; revised 5 July 2006; accepted 15 July 2006
*Corresponding author. Tel: +49-511-532-3661; Fax: +49-511-532-3353; E-mail: burkhardt.olaf{at}mh-hannover.de
Objectives: Once-daily administration of aminoglycosides in cystic fibrosis (CF) patients is considered equally efficacious and potentially less nephrotoxic than dosing three times a day. However, the choice of the most suitable PK/PD index (Cmax/MIC versus AUC24/MIC) to ensure optimum clinical outcome in this patient population is not clear.
Patients and methods: In a single-centre, open, randomized, controlled, non-blinded study 33 adult CF patients (20 females, 19–37 years) were treated with intravenous tobramycin (10 mg/kg/day) for 14 days given either as single dose once a day (Q24; 17 patients) or divided into three equal doses every 8 h (Q8; 16 patients). Tobramycin serum concentrations and MICs for Pseudomonas aeruginosa were determined on days 1 and 14. The clinical outcome parameter, correlated to PK/PD indices, was the percentage predicted forced expiratory volume in 1 s (FEV1% pred.).
Results: FEV1% pred. improved significantly for both treatments. There was a log-linear relationship between Cmax/MIC and FEV1% pred. and AUC/MIC and FEV1% pred. for both treatments. For equal values of AUC24/MIC, however, Q24 treatment provided better improvement in lung function than Q8 dosing, whereas Cmax/MIC did not show any dosing interval dependence. A statistically significant increase was observed for MIC (day 1) versus MIC (day 14) for Q24 treatment, however, no such difference was observed for Q8 treatment.
Conclusions: The most important PK/PD parameter for clinical outcome in CF patients was Cmax/MIC. Outcome prediction of AUC24/MIC was dependent on the regimen. The increase of P. aeruginosa resistance after once-daily administration is linked to a long dosing interval. More and larger studies are needed to optimize the dosing regimen for maximum clinical outcome with minimum resistance development.
Keywords: PK/PD , lung function , Pseudomonas aeruginosa
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