Increased dosage requirements of tobramycin and gentamicin for treating Pseudomonas pneumonia in patients with cystic fibrosis

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Abstract
The pharmacokinetic behavior of tobramycin and gentamicin was evaluated in 27 patients who had cystic fibrosis (CF). A previously studied, age‐matched group of 334 patients who had been treated with gentamicin and who did not have CF served as controls. The CF patients, who ranged in age from 2 to 32 years and who had normal renal function, received 36 treatment courses with either tobramycin (19) or gentamicin (17) to treat Pseudomonas pneumonia. Serum concentrations were determined after a 1.5‐mg/kg dose to compute half‐life (t1/2), elimination rate constant (k), and apparent volume of distribution (V). From these values, doses were calculated to produce steady‐state peak concentrations of 8.0 μg/ml with a dosing interval of every six hours. For tobramycin the mean (± SD) t1/2 was 1.0 (0.4) hours, V was 0.18 (0.06) I/kg, total body clearance (TBC) was 2.19 (0.71) ml/min/kg, and the calculated dose was 8.2 (2.1) mg/kg/day. For gentamicin t1/2 was 1.1 (0.5) hours, V was 0.20 (0.06) I/kg, TBC was 2.28 (0.89) ml/min/kg, and the calculated dose was 8.8 (2.4) mg/kg/day. The pharmacokinetic parameters were not statistically different between the two drugs, but the mean values of t1/2 and TBC of CF patients differed significantly from those of the control group. The calculated doses were larger than the manufacturer's maximum recommended dose of 7.5 mg/kg/day for 63% of tobramycin and 71% of gentamicin treatment courses. A dosing interval change to every four hours would have been appropriate in 28 of the 36 treatment courses (78%). There was wide interpatient and intrapatient variation in pharmacokinetic parameters, and TBC did not correlate with creatinine clearance (CLcr). CF patients require larger doses of aminoglycosides than non‐CF patients, and they must have individualized doses and dosing intervals to obtain desired drug concentrations.