Journal of Antimicrobial Chemotherapy (1999) 44, 99-108
© 1999 The British Society for Antimicrobial Chemotherapy
Isepamicin in intensive care unit patients with nosocomial pneumonia: population pharmacokinetic–pharmacodynamic study
a Departement de pharmacotoxicologie, Hôpital Avicenne, 125 route de Stalingrad, 93009 Bobigny cedex b Schering Plough, 92 rue Baudin, 92307 Levallois-Perret c Service de Réanimation Médicale, Hôpital de Tourcoing, 135 avenue du Président Coty, 59208 Tourcoing, France
A population approach was used to determine isepamicin pharmacokinetics in 196 intensive care unit patients treated for nosocomial pneumonia with isepamicin and a broad-spectrum ß-lactam. Patients were randomized in four groups with respect to the following isepamicin dosing regimens: (i) 15 mg/kg od for 5 days or (ii) 10 days, (iii) 25 mg/kg on the first day followed by 15 mg/kg od for 4 days or (iv) 9 days. A total of 1489 serum isepamicin concentrations were measured (median, eight per patient; range, 1–18). Mean ± S.D. 1 h-peak levels at day 1 were 76 ± 32 mg/L after the 25 mg/kg dose (n= 85) and 43 ± 15 mg/L after the 15 mg/kg dose (n = 99). A bicompartmental model was fitted to the data by a mixed-effect modelling approach. Isepamicin clearance was related to age, bodyweight and serum creatinine level. Central volume of distribution was related to bodyweight. Pharmacokinetic parameters were independent of the dosage in the range 15–25 mg/kg and were not different in the patients treated for 5 or 10 days. Bayesian estimates of individual pharmacokinetic parameters were used to calculate various surrogate markers of isepamicin exposure to be tentatively correlated with clinical outcome and nephrotoxicity. No correlation was found between peak, AUC or their ratio with MIC and clinical efficacy. A weak correlation was found between the increase of serum creatinine level (day 1 versus day 5) and isepamicin 24 h trough level at day 1 (R2 = 0.10). These data do not favour a systematic therapeutic monitoring of isepamicin in intensive care unit patients, at least with the doses and antibiotic combinations used in this study.
Corresponding author. Tel: +33-1-48-95-56-61; Fax: +33-1-48-95-56-59; E-mail: michel.tod{at}avc.ap-hop-paris.fr
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