JAC Advance Access published online on August 2, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl328
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1 Department of Pulmonary Medicine, Medical School Hannover, Hannover, Germany; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, USA
* To whom correspondence should be addressed. 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.
Received November 10, 2005
Revised July 5, 2006
Accepted July 15, 2006
Original article
Once-daily tobramycin in cystic fibrosis: better for clinical outcome than thrice-daily tobramycin but more resistance development?
Olaf Burkhardt 1 * 
, Christine Lehmann 2 , Rajanikanth Madabushi 3, Vipul Kumar 3, Hartmut Derendorf 3, and Tobias Welte 2
2 Department of Pulmonary Medicine, Medical School Hannover, Hannover, Germany
3 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, USA
Olaf Burkhardt, E-mail: burkhardt.olaf{at}mh-hannover.de
Abstract These authors contributed equally to this work.
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