Pharmacokinetic-Pharmacodynamic Relationship of Arbekacin for Treatment of Patients Infected with Methicillin-Resistant Staphylococcus aureus

Autor: Mitsuo Kaku, Yusuke Tanigawara, Kihachiro Shimizu, Naoki Aikawa, Reiko Sato
Rok vydání: 2006
Předmět:
Zdroj: Antimicrobial Agents and Chemotherapy. 50:3763-3769
ISSN: 1098-6596
0066-4804
Popis: Methicillin-resistant Staphylococcus aureus (MRSA) bacteria have acquired stable resistance against most clinically available antibiotics. At present, MRSA infection is treated mainly with vancomycin. However, clinical isolates of S. aureus with reduced susceptibility to vancomycin, known as glycopeptide-intermediate S. aureus or vancomycin-intermediate S. aureus have recently been reported in Japan, the United States, and Europe (5, 16, 20). On the other hand, in Japan, arbekacin has been successfully used to treat MRSA infections for more than 10 years. Arbekacin, a derivative of dibekacin, is active against MRSA and both gram-positive and gram-negative bacteria (8). Moreover, arbekacin is not affected by the inactivating enzymes produced by MRSA (9). A killing curve study demonstrated that the bactericidal activity of arbekacin depended critically on its concentration (1). As with other aminoglycosides, arbekacin is eliminated exclusively into the urine as the unchanged form via glomerular filtration and tubular reabsorption. There is a linear relationship between arbekacin pharmacokinetics and the glomerular filtration rate (4). Although therapeutic drug monitoring (TDM) of arbekacin has become a common practice to maintain drug concentrations within a therapeutic range, the target concentrations of arbekacin used to monitor efficacy and toxicity are determined simply on the basis of knowledge of other aminoglycosides, such as gentamicin, amikacin, and tobramycin (12, 15, 22). To date, the exposure-response relationship for arbekacin in patients infected with MRSA has not been established. For aminoglycosides, there is evidence that the efficacy in patients with gram-negative bacterial infections is influenced by the early onset of a high peak concentration/MIC ratio (3, 6, 7, 11). In these studies, to estimate the correlation of pharmacokinetic-pharmacodynamic indices with therapeutic outcomes in patients receiving aminoglycosides, the peak concentration was obtained from measurements 1 h after infusion (11) or extrapolated from the actual concentration obtained approximately 30 min after the end of a 30-minute infusion (3, 6, 7). In the companion article (21), we reported the population pharmacokinetic parameters of arbekacin for patients infected with MRSA. Once population pharmacokinetic parameters have been obtained, the Bayesian forecasting method is applicable for predicting the serum drug concentration-time curve in each patient on the basis of a limited number of drug concentration measurements. These predicted serum drug concentration profiles are useful to estimate individual exposure parameters to arbekacin and to analyze the relationship between exposure and response. In the present study, we analyzed the pharmacokinetic-pharmacodynamic relationship of arbekacin to determine the drug exposure parameters that correlate with the efficacy and safety of this drug and to obtain the optimal target values of these parameters. (This work was presented in part at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, 14 to 17 September 2003.)
Databáze: OpenAIRE
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